EA035020B1 - Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme - Google Patents

Abstract

A compound that inhibits ubiquitin-activating enzyme (UAE), which is (rac)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate or one of enantiomers thereof ((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate or ((1S,2S,3R,4S)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate of the following structures:or a pharmaceutically acceptable salt thereof. These compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers.

Description

State of the art

This application claims priority based on a provisional application from the United States with registration number 61/600070, filed February 17, 2012.

Ubiquitin is a small protein of 76 amino acids that is the founder of a family of post-translational modifiers known as ubiquitin-like proteins (Ubl). Ubl play a key role in the management of many biological processes, including cell division, cell signal transmission and the immune response. Ubl are small proteins that are covalently attached to lysine on a target protein through an isopeptide bond to the C terminal residue of ubl glycine. The Ubl molecule changes the molecular surface of the target protein and can affect properties such as protein-protein interactions, enzyme activity, stability, and cellular localization of the target.

There are 8 known human Ubl-activating enzymes (known as E1) (Schulman BA, and JW Harper, 2009, Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signaling pathways, Nat Rev Mol Cell Biol 10: 319-331) . Ubiquitin and other ubl are activated by a special enzyme E1, which catalyzes the formation of an intermediate compound of acyl adenylate with the C-terminal residue of glycine ubl. The activated ubl molecule is then transferred to the catalytic cysteine residue within the E1 enzyme via the formation of an intermediate thioether bond. The intermediate E1-ubl and E2 interact, resulting in a thioether exchange, with ubl being transferred to the active site of cysteine E2. Then ubl is conjugated to the target protein, either directly or together with E3 ligase, through the formation of an isopeptide bond with the amino group of the lysine side bond in the target protein. In eukaryotic cells, -35 ubiquitin E2 enzymes and> 500 ubiquitin E2 enzymes are present. Enzymes E3 are specificity factors for the ubiquitin pathway that mediates the selective delivery of specific cellular substrate proteins (Deshaies RJ and CA Joazeiro, 2009, RING domain E3 ubiquitin ligases, Annu Rev Biochem 78: 399-434; Lipkowitz S. and AM Weissman, 2011, RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumor suppression and oncogenesis, Nat Rev Cancer 1 1: 629-643; Rotin, D., and S. Kumar, 2009, Physiological functions of the HECT family of ubiquitin ligases, Nat Rev Mol Cell Biol 10: 398-409).

Two E1 enzymes were identified for ubiquitin, UAE (ubiquitin activating enzyme) and UBA6 (Jin, J., et al., 2007, Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging, Nature 447: 1135-1138). UAE is an E1 enzyme responsible for most of the uptake of ubiquitin into the cell. A UAE capable of being responsible for each of approximately ~ 35 E2 enzymes, except for use 1, in which only the E2 enzyme is known to work exclusively with UBA6 (Jin et al., 2007). UAE inhibition is sufficient to substantially worsen the vast majority of ubiquitin-dependent cellular processes (Ciechanover A., et al., 1984, Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85, Cell 37: 57-66; Finley D. , A. et al., 1984, Thermolability of ubiquitin-activating enzyme from the mammalian cell cycle mutant ts85, Cell 37: 43-55).

The cellular signals created by ubiquitin are different from each other. Ubiquitin can be attached to substrates as a single particle or as polyubiquitin polymers created through isopeptide bonds between the C-terminal residue of one ubiquitin and one of many lysines on the second ubiquitin. These various modifications are transmitted in a number of cellular signals. For example, conjugation of a 48-linked polyubiquitin chain of lysine to a substrate protein is predominantly associated with targeted action on the protein to be removed using the 26S proteasome. A single modification of ubiquitin, or monoubiquitination, usually affects protein localization and / or function. For example, monoubiquitination models the function of histones 2a and 2b (Chandrasekharan MB, et al., 2010, Histone H2B ubiquitination and beyond: Regulation of nucleosome stability, chromatin dynamics and the trans-histone H3 methylation, Epigenetics 5: 460-468), controls nuclear cytoplasmic PTEN transport (Trotman, LC, et al., 2007, Ubiquitination regulates PTEN nuclear import and tumor suppression, Cell 128: 141-156), regulates the localization of the FANCD2 protein to DNA damage sites (Gregory RC, et al., 2003, Regulation of the Fanconi anemia pathway by monoubiquitination, Semin Cancer Biol 13: 77-82) and stimulates the internalization and endosomal / lysosomal turnover of some cell surface receptors such as EGFR (Mosesson Y. and Y. Yarden, 2006, Monoubiquitylation: a recurrent theme in membrane protein transport. Isr Med Assoc J 8: 233-237). Other forms of polyubiquitination include lysine chains 11, 29, and 63, which play various roles in the cell, including the cell cycle, DNA repair, and autophagy (Behrends, C., and JW Harper, 2011, Constructing and decoding unconventional ubiquitin chains, Nat Struct Mol Biol 18: 520-528; Bennett EJ, and JW Harper, 2008, DNA damage: ubiquitin marks the spot, Nat Struct Mol Biol 15: 20-22; Komander, D., 2009, The emerging complexity of protein ubiquitination, Biochem Soc Trans 37: 937-953).

The conjugation of UAE-initiated ubiquitin plays an important role in protein homeostasis, transfer of cell surface receptors, turnover of transcription factors, and cell cycle development. Many of these processes are important for the survival of cancer cells and it is believed that tumor cells could increase sensitivity to UAE inhibition as a result of their rapid

- 1 035020 growth, increased metabolic needs and stress of proteins filled with oncogenes. Impaired protein homeostasis is a valid therapeutic approach for treating cancer. VELCADE® (bortezomib) disrupts cellular protein homeostasis and is approved for the treatment of myeloma and lymphoma from mantle cells. MLN4924, an E1 inhibitor of NeddS-activating enzyme (AE), is currently undergoing clinical oncology trials (Soucy TA, et al., 2009, An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer, Nature 458: 732-736 ; Soucy, TA, et al., 2009, Targeting NEDD8-activated cullin-RI Gigases for the treatment of cancer, Clin Cancer Res 15: 3912-3916) and numerous other goals in the field of ubiquitin / protein homeostasis are of interest for oncology ( Nalepa G., et al., 2006, Drug discovery in the ubiquitin-proteasome system, Nat Rev Drug Discov 5: 596-613). Preclinical studies regarding the PYZD-4409, UAE inhibitor, showed that it causes cell death in both leukemia cell lines and myeloma cell lines and shows antitumor activity in a mouse affected by acute myelogenous leukemia (AML model). (Xu W. G., et al., 2010, The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma, Blood, 115: 2251-59). Thus, UAE represents a new key opportunity for protein homeostasis for cancer treatment.

It is believed that UAE inhibitors will also be applicable for the treatment of diseases and conditions other than cancer, due to the extensive role of ubiquitin in cellular processes; for example, proteasome inhibitors, which, like UAE inhibitors, alter cellular protein homeostasis, offer promise for treating antibody-mediated rejection rejection (Woodle, ES, et al., 2011, Proteasome inhibitor treatment of antibody-mediated allograft rejection, Curr Opin Organ Transplant 16: 434438) , ischemic brain injury, infection, and autoimmune disorders (Kisselev, AF, et al., 2012, Proteasome inhibitors: an expanding army attacking a unique target, Chem Biol 19: 99-115). Ubiquitin-dependent signaling and degradation are important for activating pro-inflammatory pathways, such as the NF-κΒ pathway, including UAE inhibitors as possible anti-inflammatory agents (Wertz, IE, and Dixit, VM, 2010, Signaling to NF-kappaB: regulation by ubiquitination , Cold Spring Harb Perspect Biol, 2: a003350).

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a compound comprising (rac) (2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate or one of its enantiomers ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3 (trifluoromethylthio ^ enyl ^ irazolo ^^^ pyrimidine ^ -amino ^ iclopenti ^ methyl sulfamate or ((1S, 2S, 3R, 4S) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate of the following structures :

or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention relates to a pharmaceutical composition suitable for inhibiting the activity of a ubiquitin activating enzyme (UAE) comprising a compound of the invention and a pharmaceutically acceptable carrier.

In one aspect, the present invention relates to the use of a compound of the invention in the treatment of cancer in a patient in need of such treatment.

Brief Description of the Drawings

In FIG. 1 illustrates an X-ray powder (XRPD) diffraction pattern for crystalline form 1 of anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo ^^ ^ pyrimidine ^ -ylamino ^ iclopentyl ^ ethyl sulfamate.

In FIG. 2 illustrates a differential scanning calorimetry (DSC) thermogram for crystalline form 1 of anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio ^ enyl ^ irazolo ^ ^^ pyrimidine ^ -ylamino ^ iclopentyl ^ ethyl sulfamate.

In FIG. 3 illustrates a thermogravimetric analysis (TGA) thermogram for crystalline form 1 of anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1 , 5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

In FIG. 4 illustrates a Raman diffraction pattern for crystalline form 1 of anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a ] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

In FIG. 5A, a Raman diffraction pattern is illustrated within 1450 cm ⁻¹ ′ 1520 cm ⁻¹ for crystalline form 1 of anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- ( trifluoromethylthio ^ enyl ^ irazolo ^^^ pyrimidine ^ -amino ^ cyclopentyl ^ ethyl sulfamate.

In FIG. 5B, a Raman diffraction pattern is illustrated within 1450 cm ⁻¹ −1520 cm ⁻¹ for crystalline form 2 monohydrated (8..e.) - ((1K, 2K, 38.4K) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

In FIG. 6A illustrates a Raman diffraction pattern within 1100 cm ⁻¹ −1240 cm ⁻¹ for crystalline form 1 of anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- ( trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

In FIG. 6B illustrates a Raman diffraction pattern in the range of 1 100 cm ⁻¹ −1240 cm ⁻¹ for crystalline form 2 of monohydrated (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5s] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

In FIG. 7A, a Raman diffraction pattern is illustrated within 700 cm ⁻¹ −1100 cm ⁻¹ for crystalline form 1 of anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- ( trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

In FIG. 7B, a Raman diffraction pattern is illustrated within 700 cm ⁻¹ −1100 cm ⁻¹ for crystalline form 2 of monohydrated (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- ( trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

In FIG. Figure 8 illustrates an X-ray powder (XRPD) diffraction pattern for crystalline form 2 of monohydrated (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1 , 5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

In FIG. 9 illustrates a differential scanning calorimetry (DSC) thermogram for crystalline form 2 of monohydrated (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3 (trifluoromethylthio) phenyl) pyrazolo [1 , 5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

In FIG. 10 illustrates a thermogram of thermogravimetric analysis (TGA) for crystalline form 2 of monohydrated (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1 , 5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

In FIG. 11 illustrates a Raman diffraction pattern for crystalline form 2 of monohydrated (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a ] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate.

DETAILED DESCRIPTION OF THE INVENTION Definitions Chemical Compounds

Unless a stereochemical configuration is indicated, the structures depicted in this document are intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each center of asymmetry. Thus, unless otherwise indicated, individual stereochemical isomers, as well as enantiomeric, racemic and diastereoisomeric mixtures of the present chemical compounds are included in the scope of the present invention.

As used herein, crystalline refers to a solid in which constituent atoms, molecules or ions are packed in a regularly ordered, repeating three-dimensional model having an extremely constant chemical structure. In particular, a crystalline compound or salt can be obtained in the form of one or more crystalline forms. For the purposes of the present invention, the terms crystalline form and polymorph are synonymous; the terms distinguish between crystals that have different properties (for example, different XRPD patterns, different DSC scans). Pseudopolymorphs are usually different solvates of the material, and thus the properties of pseudopolymorphs are different from each other. Thus, it is believed that each different polymorph and pseudopolymorph is a different crystalline form in this document.

In essence, crystalline refers to compounds or salts that are at least crystalline in a single weight percent. In some embodiments, the compound or salt is substantially crystalline. Examples of the crystalline form or essentially the crystalline form include a single crystalline form or a mixture of various crystalline forms. Individual percentages by weight include 50, 60, 70, 75, 80, 85, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 and 99.9 % In some embodiments, essentially crystalline refers to compounds or salts that are at least 70% crystalline. In some embodiments, essentially crystalline refers to compounds or salts that are at least 80% crystalline. In some embodiments, essentially crystalline refers to compounds or salts that are at least 85% crystalline. In some embodiments, essentially crystalline refers to compounds or salts that are at least 90% crystalline. In some embodiments, essentially crystalline refers to compounds or salts that are at least 95% crystalline.

The term seed refers to the addition of crystalline material to a solution or mixture to cause crystallization.

Some embodiments of the present invention are directed to compounds or salts, where at least a separate percentage by weight of the compound or salt is crystalline. Some embodiments of the present invention are directed to a compound or salt, wherein at least a single percent by weight of the compound or salt is crystalline. Individual percentages by weight include 10, 20, 30, 40, 50, 60, 70, 75, 80, 85, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 %, 99.5 and 99.9%. When a single percent by weight of the compound or salt is crystalline, the remainder of the compound or salt is an amorphous form of the compound or salt. When a single percent by weight of the compound or salt is the named crystalline form, the remainder of the compound or salt is some combination of an amorphous form of the compound or salt, and one or more crystalline forms of the compound or salt, not including the named crystalline form.

When the crystalline form of a compound or salt is determined using one or more XRPD peaks obtained as 2θ angles, it is clear that each of the 2θ values means the resulting value is ± 0.2 degrees, unless otherwise indicated, for example, as the resulting value is ± 0.3 .

When the crystalline form of a compound or salt is determined using one or more temperatures from the DSC profile (for example, the onset of an endothermic transition, melting, etc.), it is clear that each of the temperature values means the resulting value is ± 2 ° C.

When the crystalline form of the compound or salt is determined using one or more peaks from the Raman diffraction pattern, expressed in cm ^-1 , it is clear that it means the obtained value of ± 0.2 cm ^-1 , unless otherwise indicated.

Examples of chemical compounds of the present invention include the following: (rac) - (2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate, or one of its enantiomers ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7 -ylamino ) cyclopentyl) methyl sulfamate, or ((1S, 2S, 3R, 4S) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl ) methyl sulfamate of the following structures:

is ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethyl) A compound representing thio ^ ene ^ pyrazolo ^^^ pyrimidine ^ -amino ^ cyclopentyl ^ ethyl sulfamate of the formula I- 101

General synthetic methods

These and other compounds of chemical compounds of the present invention can be obtained by methods known to a person skilled in the art, and / or by reference to the schemes shown below, and / or by reference to the procedures described in the examples below.

Scheme 1. General method for 2-substituted ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (pyrazolo [1,5a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamates

A general method for the synthesis of compounds represented by structure iv, wherein Z is

- 4 035020 an optionally substituted fused or non-fused aryl or heteroaryl ring described above in Scheme 1. Compound i (prepared by coupling an appropriately protected cyclopentylamine or salt thereof with 2-bromo-7-chloropyrazolo [1,5-c] pyrimidine in the presence of a suitable the bases, as described below in the procedure of examples 1a and 1b), are converted to a compound of formula iii by coupling to a substituted metal compound ZM via a palladium-catalyzed reaction. A compound of formula iii can also be prepared by first converting i to a substituted compound of the metals of formula ii using suitable boron or tin containing reagents, and then linking to the substituted halogen compound Z-X via a palladium-catalyzed reaction. Compounds of formula iv were then prepared by reaction with a suitable sulfamating reagent (e.g., chlorosulfonamide or see Armitage, I. et. Al. U.S. Patent Document 2009/0036678 and Armitage, I. et al. Org. Lett., 2012, 14 (10 ), 2626-2629), followed by suitable conditions for deprotection.

Scheme 2: General method for 5-halogen-substituted, 2-substituted ((III, 2K, 38.4K) -2,3-dihydroxy-4 (pyrazolo [1,5-a | i shrimid 1-7 -amino) cyclopentyl) methyl sulfamates

CM X

A general method for synthesizing compounds represented by structure iv, wherein Z is an optionally substituted fused or non-fused aryl or heteroaryl ring and X is a halogen is described above in Scheme 2. Cyclization of aminopyrazole v with an acceptable diester and a suitable base at elevated temperature, followed by reaction with a suitable halogenating reagent, such as POCl ₃ , at elevated temperature to give compounds of formula vii. Then the compounds of formula viii were obtained by reaction with a suitable protected cyclopentylamine or its salt in the presence of an acceptable base. Sulfamination and deprotection followed by method 1, as described above, provide compounds of formula ix.

Scheme 3: General method for 5-alkyl substituted, 2-substituted ((III, 2K, 38.4K) -2,3-dihydroxy-4 (pyrazolo [1,5-a | i shrimid 1-7 -amino) cyclopentyl) methyl sulfamates

A general method for synthesizing compounds represented by structure xiii, wherein Z is an optionally substituted fused or non-fused aryl or heteroaryl ring, and R is an alkyl substituent, is described above in Scheme 3. Cyclization of aminopyrazole v with an acceptable substituted β-keto ester at elevated a temperature followed by reaction with a suitable halogenating reagent such as POCl ₃ ; at elevated temperature to give compounds of formula xi. Then the compounds of formula xii were obtained by reaction with a suitable protected cyclopentylamine or its salt in the presence of an acceptable base. Sulfamination and deprotection followed by method 1, as described above, provide compounds of formula xiii.

Solid phase forms

The selection of characterizing information presented in this document that is sufficient, but not all necessary, to describe the crystalline form 1 of anhydrous compound 1101 ((se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl) methyl sulfamate (Form 1).

In FIG. 1 illustrates an X-ray powder diffractogram (XRPD) of Form 1 of compound 1-101 obtained using CuKa radiation. The peaks indicated in FIG. 1 include those listed in table. 1.

- 5 035020

In some embodiments, Form 1 is characterized by an XRPD diffraction pattern having a peak at a 2θ angle of 20.7 °. In some embodiments, Form 1 is characterized by an XRPD diffraction pattern having peaks at 2θ angles of 20.5 ° and 20.7 °. In some embodiments, Form 1 is characterized by an XRPD diffraction pattern having peaks at 2θ angles of 16.4 °, 18.0 °, 20.5 °, and 20.7 °. In some embodiments, Form 1 is characterized by an XRPD pattern having peaks at 2θ angles of 14.8 °, 16.4 °, 18.0 °, 19.1 °, 20.5 °, 20.7 ° and 23.6 °. In some embodiments, Form 1 is characterized by an XRPD pattern having peaks at 2θ angles of 13.6 °, 14.8 °, 16.4 °, 18.0 °, 19.1 °, 20.5 °, 20.7 °, 21.3 °, 23.6 °, 24.6 ° and 31.8 °. In some embodiments, Form 1 is characterized by an XRPD diffraction pattern, generally as illustrated in FIG. 1.

In some embodiments, Form 1 is characterized by an XRPD pattern having an initial peak with a 2θ angle of 16.4 ± 0.3 °, and having peaks at 2θ angles of 1.6 °, 4, and 4.3 ° relative to the original peak. The term source peak refers to the peak in the XRPD diffractogram, which is considered to be specialist in the art representing information about the polymorphic shape of the material, for example, distinguishing from hardware noise. By relative is meant that the measured angle 2θ of each peak will be the sum of the angle 2θ of the original peak and the relative angle 2θ of this peak. For example, if the original peak has an angle of 2θ of 16.3 °, the relative peaks will have angles of 2θ

17.9 °, 20.4 ° and 20.6 °; if the original peak has an angle of 2θ of 16.4 °, the relative peaks will have angles of 2θ

18.0 °, 20.5 ° and 20.7 °; if the original peak has a 2θ angle of 16.5 °, the relative peaks will have 2θ angles

18.1 °, 20.6 ° and 20.8 °; etc. In some embodiments, Form 1 is characterized by an XRPD diffraction pattern having an initial peak at a 2θ angle of 16.4 ± 0.3 ° and having peaks at a 2θ angle of -1.6 °, 1.6 °, 2.7 °, 4.1 ° , 4.3 ° and 7.2 ° relative to the original peak. In some embodiments, Form 1 is characterized by an XRPD diffraction pattern having an initial peak with a 2θ angle of 16.4 ± 0.3 ° and peaks at 2θ angles of -2.8 °, -1.6 °, 1.6 °, 2.7 °, 4.1 °, 4.3 °, 4.9 °, 7.2 °, 8.2 ° and 15.4 ° relative to the initial peak. Any of the peaks that are considered to be representative of the polymorphic form of the material by a person skilled in the art can serve as an initial peak, and thus relative peaks can be calculated. For example, if the original peak has an angle of 2θ of 20.7 °, then the relative peaks will have angles of 2θ -4.3 °, -2.7 ° and -0.2 ° relative to the original peak.

In FIG. 2 illustrates a differential scanning calorimetry (DSC) profile of Form 1 of Compound 1-101. The differential scanning calorimetry thermogram plots the heat flux curve as a function of temperature from the sample, the temperature ratio changes at a speed of approximately 10 ° C / min. In some embodiments, Form 1 is characterized by a DSC profile, mainly as illustrated in FIG. 2. In FIG. 2 illustrates an exotherm with an onset of approximately 192.3 ° C and a peak at approximately 195.3 ° C.

In FIG. 3 illustrates the thermogravimetric analysis (TGA) profile of form 1 of compound 1-101. The thermogram of thermogravimetric analysis TGA plots the curve of the percentage weight loss of the sample as a function of temperature, the temperature ratio changes at a speed of approximately 10 ° C7min. In FIG. 3 illustrates approximately 0.4% weight loss up to 120 ° C. In some embodiments, Form 1 is characterized by a TGA thermogravimetric analysis profile, mainly as illustrated in FIG. 3. Karl Fischer measurements of Form 1 show a water content of approximately 0.7%.

In FIG. 4 illustrates a Raman diffraction pattern of Form 1 of compound 1-101. In some embodiments, Form 1 is characterized by a Raman diffraction pattern, mainly as illustrated in FIG. 4. The peaks indicated in FIG. 4 in the area from 55 cm ^-1 to 1800 cm ^-1 include those

- 6 035020 numerical in the table. 2 below. In FIG. 5A illustrates a Raman diffraction pattern of Form 1 of compound 1-101 in the region of 1450 cm ^-1 to 1520 cm ^-1 . In some embodiments, the implementation of form 1 is characterized by a peak at 1469.1 cm ^-1 . In FIG. 6A illustrates a Raman diffraction pattern of Form 1 of compound 1101 in the region of 1100 cm ^-1 to 1240 cm ^-1 . In some embodiments, Form 1 is characterized by a Raman diffraction pattern, mainly as illustrated in FIG. 6A. In some embodiments, Form 1 is characterized by a peak at 1200.2 cm ⁻¹ . In FIG. 7A illustrates a Raman diffraction pattern of Form 1 of compound 1-101 in the region of about 700 cm ^-1 to about 1,100 cm ^-1 . In some embodiments, Form 1 is characterized by a Raman diffraction pattern, mainly as illustrated in FIG. 7A. In some embodiments, Form 1 is characterized by peaks at 1059.3, 954.7, 845.3, and 805.2 cm ⁻¹ . In some embodiments, Form 1 is characterized by peaks at 954.7 and 805.2 cm ^-1 .

table 2

Peak (cm ' ¹ ) Intensity 62.7 1057.18 93,4 1047.64 109.8 1069.98 193.2 340.36 226.8 158.25 266.3 26.10 283.1 65.41 308.3 51.53 353.1 71.31 425.3 61.00 469.9 65.13 545.2 64.03 595.1 45.09 639.9 188.46 707.5 166.50 752.4 105.67 771.8 92.90 805.2 466.55 845.3 113.29 954.7 466.61 986.8 70,99 997.9 775.23 1059.3 66.37 1075.1 34.74 1101.2 38.50 1166.9 76,42 1200,2 218.72 1302.3 295.74 1345.0 886.09 1440.9 957.45 1469.1 116.07 1503.7 1098.73 1541.6 98.76 1601.4 2315.65

In some embodiments, the implementation of form 1 of compound 1-101 is characterized by at least one of the following properties (I-i) - (I-iv):

(I-i) an XRPD diffraction pattern having peak angles 2θ of 16.4 °, 18.0 °, 20.5 ° and 20.7 °, as illustrated in FIG. 1;

(1st) DSC profile, mainly as illustrated in FIG. 2;

(I-iii) a TGA profile, mainly as illustrated in FIG. 3;

(I-iv) a Raman diffraction pattern, mainly as illustrated in FIG. 4;

In some embodiments, Form 1 is characterized by at least two of the properties (I-i) to (I-iv). In some embodiments, Form 1 is characterized by at least three of the properties (I-i) to (I-iv). In some embodiments, Form 1 is characterized by all four of the properties (I-i) - (I-iv).

The selection of characterizing information presented in this document that is sufficient, but not all necessary, to describe the crystalline form 2 of the monohydrated compound 1-101 ((se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy- 4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate (form 2).

In FIG. 8 illustrates a X-ray powder diffraction pattern (XRPD) of crystalline form 2 of monohydrated compound 1-101 obtained using CuKa radiation. The peaks indicated in FIG. 8 include those listed in table. 3.

- 7 035020

In some embodiments, Form 2 is characterized by an XRPD diffraction pattern having peaks at angles of 2 · 6.7 °, 17.6 °, 20.0 °, and 21.6 °. In some embodiments, Form 2 is characterized by an XRPD diffraction pattern having peaks at angles of 2 · 6.7 °, 11.5 °, 17.6 °, 19.1 °, 20.0 °, 21.6 °, 23.1 °, and 23.3 °. In some embodiments, Form 2 is characterized by an XRPD diffraction pattern having peaks at angles of 2 · 6.7 °, 11.5 °, 15.2 °, 16.6 °, 17.6 °, 19.1 °, 20.0 °, 20.3 °, 21.6 °, 23.1 °, 23.3 ° and 25.4 °. In some embodiments, Form 2 is characterized by an XRPD diffraction pattern, mainly as illustrated in FIG. 8.

In some embodiments, Form 2 is characterized by an XRPD diffractogram having an initial peak at an angle of 2 ° 6.7 ± 0.3 °, and having peaks at angles of 2 ° 10.9 °, 13.3 °, and 14.9 ° relative to the initial peak. The terms initial peak and relative have the same meaning as described above. In some embodiments, Form 2 is characterized by an XRPD diffraction pattern having an initial peak at an angle of 2Θ 6.7 ± 0.3 ° and peaks at angles of 2Θ 4.8 °, 10.9 °, 12.4 °, 13.3 °, 14.9 °, 16.4 ° and 16.6 ° relative to the original peak. In some embodiments, Form 2 is characterized by an XRPD diffraction pattern having an initial peak with a 2Θ angle of 2Θ 6.7 ± 0.3 ° and peaks at 2 ° 4.8 °, 8.5 °, 9.9 °, 10.9 °, 12.4 °, 13.3 °, 13.6 °, 14.9 °, 16.4 °, 16.6 ° and 18.7 ° relative to the initial peak. Any of the peaks that are considered to be representative of the polymorphic form of the material by a person skilled in the art can serve as an initial peak, and thus relative peaks can be calculated. For example, if the original peak has an angle of 2Θ 20.0 °, then the relative peaks will have angles of 2Θ -13.3 °, -2.4 ° and 1.6 ° relative to the original peak.

In FIG. 9 illustrates a differential scanning calorimetry (DSC) profile of form 2 of compound 1-101. The differential scanning calorimetry thermogram plots the heat flux curve as a function of temperature from the sample, the temperature ratio changes at a speed of about 10 ^ / min. In some embodiments, Form 2 is characterized by a DSC profile, mainly as illustrated in FIG. 9. In FIG. 9 illustrates an endotherm with a start at about 81.2 ° C and a peak at about 108.3 ° C, in accordance with the loss of water that follows the endotherm with a start at about 151.1 ° C and a peak at about 153.2 ° C.

In FIG. 10 illustrates a thermogravimetric analysis (TGA) profile of Form 2 of Compound 1-101. TGA thermogravimetric thermogram plotting percent weight loss curve

- 8 035020 of the sample as a function of temperature, the temperature ratio changes at a speed of approximately 10 ° C / min. In FIG. 10 illustrates approximately 3.1% weight loss (w / w) up to 120 ° C., suggesting that Form 2 is a monohydrate. In some embodiments, Form 2 of Compound 1-101 is characterized by a TGA profile, mainly as illustrated in FIG. 10. Karl Fischer measurements of form 2 of compound 1-101 show a water content of approximately 2.9%, further confirming that form 2 is a monohydrate.

In FIG. 11 illustrates a Raman diffraction pattern of Form 2 of compound 1-101. In some embodiments, Form 2 is characterized by a Raman diffraction pattern, mainly as illustrated in FIG. 11. The peaks indicated in FIG. 11 in the range from 55 cm ^-1 to 1800 cm ^-1 include those listed in the table. 4 below. In FIG. 5B illustrates a Raman diffraction pattern of Form 2 of compound 1-101 in the region of 1450 cm ^-1 to 1520 cm ^-1 . In FIG. 6B illustrates a Raman diffraction pattern of Form 2 of compound 1-101 in the region of 1100 cm ^-1 to 1240 cm ^-1 . In some embodiments, Form 1 is characterized by a Raman diffraction pattern, mainly as illustrated in FIG. 6B. In some embodiments, implementation of form 1 is characterized by a peak at 1205.4 cm ^-1 . In FIG. 7B illustrates a Raman diffraction pattern of Form 2 of compound 1-101 in the region of about 700 cm ^-1 to about 1100 cm ^-1 . In some embodiments, Form 2 is characterized by a Raman diffraction pattern, mainly as illustrated in FIG. 7B. In some embodiments, Form 2 is characterized by peaks at 958.7 and 923.2 cm ⁻¹ .

Table 4

Peak (cm ^-1 ) Intensity 60 839,324 94.7 813,247 190.4 123.76 216.8 61.08 285.5 35.40 353.7 27.34 424.4 21.79 470.9 28.93 545.7 28.08 640.5 97.91 707.4 59.11 753.4 51.10 773.9 35.84 809.9 163.67 923.2 26.66 958.7 175.20 997.9 281.45 1068.5 22.13 1167.8 26.59 1205.4 79.16 1302.2 147.41 1343.7 278.22 1442.1 309.65 1504.6 325.60 1542.4 39.61 1571.0 34.15 1599.3 768.82

In some embodiments, the implementation of form 2 of compound 1-101 is characterized by at least one of the following properties (I-v) - (I-viii):

(I-v) an XRPD diffraction pattern having peaks of angles 2θ of 6.7 °, 17.6 °, 20.0 ° and 21.6 °, as illustrated in FIG. 8;

(I-vi) a DSC profile, mainly as illustrated in FIG. 9; (I-vii) TGA profile, mainly as illustrated in FIG. 10;

(I-viii) Raman diffraction pattern, mainly as illustrated in FIG. eleven;

In some embodiments, Form 2 is characterized by at least two of properties (I-v) - (I-viii). In some embodiments, Form 2 is characterized by at least three of properties (I-v) - (I-viii). In some embodiments, Form 2 is characterized by all four of the properties (I-v) - (I-viii).

The chemical compounds of the present invention are useful inhibitors of UAE activity. Inhibitors are designed to incorporate chemical compounds that reduce the expected effects of UAE-initiated conjugation of ubiquitin with target proteins (e.g., decrease in ubiquitination), reduce intracellular signal transmission mediated by conjugation of ubiquitin, and / or reduce protein cleavage mediated by conjugation (e.g., ubiquitin conjugation, ubiquitin, cell conjugation of ubiquitin, ubiquitin-dependent signaling and ubiquitin

- 9 035020 dependent protein breakdown (e.g., ubiquitin-proteasome pathway)). Thus, the chemical compounds of the present invention can be analyzed for their ability to inhibit UAE in vitro or in vivo, either in cells or animal models according to the methods presented in more detail herein or methods known in the art. Chemical compounds can be evaluated for their ability to bind to or alter UAE activity directly. Alternatively, the activity of chemical compounds can be evaluated through indirect cell assays, or assays measuring the downstream effects of UAE of the expected acceleration of ubiquitin to evaluate inhibition of the downstream effects of UAE inhibition (e.g., inhibition of ubiquitin-dependent protein cleavage). For example, activity can be evaluated by detecting ubiquitin-conjugated substrates (eg, ubiquitin-filled E2 or ubiquitinized substrates); detecting downward stabilization of the protein substrate (e.g., c-myc stabilization, 1kV stabilization); detecting inhibition of UPP activity; detecting the downward effects of UAE inhibition and stabilization of the substrate (e.g., reporter gene assays, e.g. NFkB reporter assays, p27 reporter gene assays, or cell polyubiquitin loss assays). Assays for evaluating activities are described below in the section for examples and / or are known in the art.

Songs

Some embodiments of the present invention relate to a composition comprising a chemical compound of the present invention and a pharmaceutically acceptable carrier. Some embodiments of the present invention relate to a composition comprising a prodrug of a chemical compound of the present invention and a pharmaceutically acceptable carrier.

If the pharmaceutically acceptable salt is a chemical compound of the present invention used in these compositions, said salts are preferably derived from inorganic or organic acids and bases. To view acceptable salts, see, for example, Berge et al., J. Pharm. Sci. 66: 1-19 (1977) and Remington: The Science and Practice of Pharmacy, 20th Ed., A. Gennaro (ed.), Lippincott Williams & Wilkins (2000) Remington's).

Examples of acceptable acid addition salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorite, camphor sulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucocephanoate, hecoheptanoate hexanoate, hydrochloride, hydrobromide, hydroiodide, 2hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl propionate, picrate, pivalate, tionate, propionate, tionate, propionate, tionate, tionate, propionate, tionate, propionate, tionate, tionate, tionate, undecanoate.

Examples of suitable base addition salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohexylamine salts, -methyl-C-glucamine, and salts with amino acids such as arginine, lysine, and the like.

Also, basic nitrogen-containing groups can be quaternized by such means as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides and others. Thus, water-soluble or oil-soluble or dispersible products are obtained.

The pharmaceutical compositions of the present invention are preferably presented in a form suitable for administration to a recipient subject, preferably a mammal, more preferably a human. The term pharmaceutically acceptable carrier, as used herein, refers to a material that is compatible with the recipient subject and suitable for delivering the active substance to the target site without limiting the activity of the substance. The toxicity or side effects, if any, associated with the carrier are preferably comparable to the justified risk / expected benefit ratio for the intended use of the active substance. Many such pharmaceutically acceptable carriers are known in the art. See, for example, Remington's; Handbook of Pharmaceutical Excipients, 6th Ed., R.C. Rowe et al. (eds.), Pharmaceutical Press (2009).

The pharmaceutical compositions of the present invention can be obtained using methods well known in the art, such as conventional crushing, mixing, dissolving, encapsulating, lyophilization or emulsification methods, among others. Compositions can be presented in various forms, including granules, precipitates or particles, powders, including lyophilized powders, powders obtained with a tumble dryer or powders obtained by spray drying, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs , suspensions or solutions. The compositions may optionally contain stabilizers, pH modifiers, surfactants, solubilizing agents, bioavailability modifiers, and combinations thereof.

- 10 035020

Pharmaceutically acceptable carriers that can be used in these combinations include ion exchange agents, alumina, aluminum stearate, lecithin, whey proteins such as human serum albumin, buffering agents such as phosphates or carbonates, glycine, sorbic acid, potassium sorbate, incomplete glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen chloride, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

According to a preferred embodiment, the compositions of the present invention are formulated for pharmaceutical administration to a mammal, preferably a human. Such pharmaceutical compositions of the present invention can be administered orally, parenterally, using an inhaler, topically, rectally, nasally, vestibularly, vaginally or through an implanted reservoir. The term parenteral, as used herein, includes subcutaneous, intravenous, intraperitoneal, intramuscular, intraarticular, intraarticular, intrathoracic, intrathecal, intrahepatic, intracranial and intracranial administration or methods of infusion. Preferably, the compositions are administered orally, intravenously or subcutaneously. The compositions of the present invention can be developed as compositions of short action, quick release or long action. Still further, the compounds can be administered with a local agent rather than a systemic agent, such as introducing (for example, by injection) into the localization of the tumor.

Pharmaceutical formulations may be prepared in the form of liquid suspensions or solutions using a liquid, such as oil, water, alcohol, and combinations thereof. Solubilizing agents, such as cyclodextrins, may be included. Pharmaceutically acceptable surfactants, suspending agents or emulsifying agents may be added for oral or parenteral administration. Suspensions may include oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. The suspension preparation may also contain fatty acid esters such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as poly (ethylene glycol), petroleum hydrocarbons, such as mineral oil and petrolatum; and water can also be used in suspension formulations.

Sterile injectable forms of the compositions of the present invention may be in the form of an aqueous or oily suspension. These suspensions can be formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be in the form of a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable agents and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as a solvent or suspension medium. For these purposes, you can use any light non-volatile oil, including synthetic mono - or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, can also be used in the preparation of injectable preparations, as well as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in the form of the corresponding polyoxyethylene forms. These oil solutions or suspensions may also contain a diluent or dispersant, which is a long chain alcohol, such as carboxymethyl cellulose, or similar dispersants, which are widely used in the preparation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are widely used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms, may also be used for formulation purposes. The compounds may be formulated for parenteral administration by injection, such as a loading dose or continuous infusion. A unit dosage form for injection can be presented in ampoules or in multi-dose containers.

The pharmaceutical compositions of the present invention can be administered orally in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions or solutions. When aqueous suspensions for oral administration are required, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added. In such solid dosage forms, the active chemical compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or diluents, such as starches, lactose, sucrose, glucose , mannitol, microcree

- 11 035020 steel cellulose and silicic acid, b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, sucrose and gum arabic, c) humectants, such as glycerin, d) substances to improve the disintegration of tablets, such as agar agar, calcium carbonate, polyvinylpyrrolidinone, croscarmellose, sodium starch glycolate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution inhibiting agents such as paraffin, f) absorption accelerators such as quaternary g, such as quaternary ) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, sodium stearyl fumarate, solid polyethylene glycols, sodium lauryl silicon dioxide and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

The active chemical compound may also be presented in microencapsulated form with one or more excipients, as noted above. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings, such as enteric coatings, release control coatings and other coatings known in the art of pharmaceutical formulations. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also include, in accordance with ordinary practice, additional substances other than inert diluents, for example, tabletting lubricants and other tabletting additives, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may also be such compositions that release the active ingredient (s) only, or preferably, in a certain part of the intestine, optionally, in a delayed manner. Examples of enclosing compositions that may be used include polymeric substances and waxes.

Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. They can be obtained by mixing the product with a suitable non-irritating adjuvant, which is in the solid state at room temperature, but becomes liquid at the rectal temperature and thus melts in the rectal cavity to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the present invention can also be administered superficially, especially if the purpose of the treatment includes areas or organs that are readily accessible for topical application, including diseases of the eyes, skin, or lower gastrointestinal tract. Suitable topical formulations are readily prepared for each of these sites or organs.

Topical application for the lower gastrointestinal tract can be performed in the rectal composition of the suppository (see above) or in a suitable composition for a solution for gastric lavage. Can also use transdermal patches for topical application. For topical application, the pharmaceutical compositions can be formulated in a suitable ointment containing the active ingredient, suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions can be formulated as finely divided suspensions in an isotonic sterile salt solution with a controlled pH value or, preferably, in the form of solutions in an isotonic sterile salt solution with a controlled pH value, either in the presence or absence of a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical compositions may be formulated as an ointment, such as petrolatum.

The pharmaceutical compositions of the present invention can also be administered as a nasal aerosol or inhaler. Such compositions are prepared using methods well known in the pharmaceutical formulation field and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to increase bioavailability, fluorocarbons and / or traditional solubilizing or dispersing funds.

The pharmaceutical compositions of the present invention, in particular, are used in therapeutic applications related to disorders as described herein (e.g., disorders

- 12 035020 proliferation, for example, types of cancer, inflammatory, neurodegenerative disorders). The term subject, as used herein, means an animal, preferably a mammal, more preferably a human. The term patient, as used herein, means a person. Preferably, the composition is formulated for administration to a patient or subject suffering from or at risk of developing or experiencing a relapse of the corresponding disorder to be treated. Preferred pharmaceutical compositions of the present invention are compositions formulated for oral, intravenous or subcutaneous administration. However, any of the aforementioned dosage forms containing a therapeutically effective amount of a chemical compound of the present invention, is within the scope of the established experiments and, thus, within the scope of the present invention. In specific embodiments, the pharmaceutical composition of the present invention may further comprise another therapeutic agent. Preferably, such another therapeutic agent is one which is usually administered to a patient suffering from a disorder, disease or condition to be treated.

By a therapeutically effective amount is meant an amount of a chemical compound or composition sufficient when administered in a single or multiple doses to provide a marked reduction in UAE activity and / or severity of the disorder or condition of the disease to be treated. By a therapeutically effective amount is also meant the inclusion of a sufficient amount to treat a cell, inhibit or prevent the development of a disorder or condition of the disease that is being treated (for example, preventing the growth of additional cancer tumors, preventing an additional inflammatory reaction), improving, alleviating, alleviating or mitigating the subject's symptoms besides that expected in the absence of such treatment. The amount of UAE inhibitor needed will depend on the particular compound of the resulting composition, the type of disorder to be treated, the route of administration, and the length of time required to treat the disorder. It should also be noted that the specific dose and treatment regimen for any particular patient will depend on many factors, including the activity of the particular chemical used, age, body weight, general health, gender and diet of the patient, time of administration, rate of excretion, combination of drugs drugs, the views of the attending physician and the severity of the specific disease to be treated. In some aspects, where the inhibitor is administered in combination with another agent, the amount of the additional therapeutic agent present in the composition of the present invention will usually be no more than the amount that would normally be added to the composition containing the therapeutic agent as the only active agent. Preferably, the amount of the additional therapeutic agent will be in the range of from about 50% to about 100% of the amount usually present in the composition containing the agent as the only therapeutically active agent.

Applications

In some embodiments, the present invention relates to a method of inhibiting or reducing UAE activity in a sample, comprising contacting a chemical compound of the present invention, or a composition comprising a chemical compound of the present invention. A sample, as used herein, includes a sample containing purified or partially purified UAE, cultured cells, or cell culture extracts; biopsy cells or fluid obtained from a mammal, or extracts thereof; and body fluid (e.g., blood, serum, saliva, urine, feces, seminal fluid, tears) or extracts thereof. Inhibition of UAE activity in a sample can be carried out in vitro or in vivo, in cellulo, or in situ.

In some embodiments, the present invention provides a method of treating a patient suffering from a disorder, a symptom of a disorder that is at risk of developing or experiencing a relapse of the disorder, comprising administering to the patient a chemical compound or pharmaceutical composition according to the present invention. The implementation of the treatment may include treatment, healing, relief, mitigation, alteration, restoration, improvement, temporary relief, recovery or impact on the disease, symptoms of the disorder or tendency to disturbance. Without being bound by theory, it is believed that the implementation of the treatment inhibits the growth, ablation or killing of a cell or tissue in vitro or in vivo, or in any other way reduces the ability of a cell or tissue (e.g., an abnormal cell, an affected tissue) to cause a violation, such as a violation, such as described herein (e.g., proliferative disorder, e.g., cancer, inflammatory disorder). As used herein, inhibition of the growth of a cell or tissue (e.g., proliferative cell, tumor tissue) refers to a slowdown, interruption, retardation or arrest of its growth and metastases and does not necessarily indicate a complete cessation of growth.

UAE represents a new target opportunity for protein homeostasis to treat cancer and other human diseases where the nature of ubiquitin is present. Applications to diseases include those disorders in which inhibition of UAE activity impairs the survival and / or proliferation of cells or tissues of the disease (for example, cells are sensitive to UAE inhibition; inhibition of UAE activity interrupts the mechanisms of the disease; a decrease in UAE activity stabilizes the protein, which is an inhibitor of the mechanisms of the disease; a decrease in UAE activity results in the inhibition of proteins that are activators of the mechanisms of the disease).

Applications to diseases also include the inclusion of any disorder, disease or condition that requires effective ubiquitination activity, and this activity can be regulated by attenuating UAE activity.

For example, the methods of the present invention are useful in treating disorders, including cell proliferation, including disorders that require effective ubiquitin-ligase-dependent ubiquitination and signaling or protein cleavage (e.g., the ubiquitin-proteasome pathway) to maintain and / or progress the disease state. The methods of the present invention are useful in the treatment of protein-mediated disorders (e.g., NFkB activation, p27Kf activation, p21WAF / CIP1 activation, p53 activation) that are regulated by UAE activity. Related disorders include proliferative disorders, the most significant cancers and inflammatory disorders (e.g., rheumatoid arthritis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, dermatosis (e.g., atopic dermatitis, psoriasis), vascular proliferative disorders (e.g. , atherosclerosis, restenosis) autoimmune diseases (for example, multiple sclerosis, tissue and organ rejection)); and infection-related inflammation (e.g., immune responses), neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, motor neuron disease, neuropathic pain, triplet-recurring disorders, astrocytoma and neurodegeneration as a result of alcoholic liver disease), ischemic damage ( for example, an attack) and cachexia (for example, accelerated breakdown of muscle proteins, which is accompanied by various physiological and pathological conditions (for example, nerve damage, starvation, fever, acidosis, HIV infection, cancer and specific endocrinopathies).

The compounds and pharmaceutical compositions of the present invention are particularly useful for treating cancer. As used herein, the term cancer refers to a cell disorder characterized by uncontrolled or unregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissue and / or the ability to provide new growth in ectopic sites. The term cancer includes solid tumors and blood tumors. The term cancer covers diseases of the skin, tissues, organs, bones, cartilage, blood and blood vessels. The term cancer further encompasses primary cancer and metastatic cancer.

In some embodiments, the cancer is a solid tumor. Examples of solid tumors that can be treated by the methods of the present invention include pancreatic cancer; bladder cancer; colon and rectal cancer; colorectal cancer, breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; hepatocellular cancer; bronchial and lung cancer, including, for example, non-small cell lung cancer (NSCLC), squamous lung cancer, small cell lung cancer (SCLC), bronchioalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial or primary peritoneal cancer; cervical cancer; endometrial cancer, bladder cancer, stomach cancer; esophageal carcinoma; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck, nasopharyngeal cancer, oral cancer and thyroid cancer, melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, anaplastic oligodendroglioma, glioblastoma multiforme, and anaplastic astrocytoma; bone cancer and soft tissue sarcoma.

In some embodiments, the cancer is a hematologic malignant tumor. Examples of hematologic malignancies include acute myelocytic leukemia (AML); chronic myelogenous leukemia (CML), including the accelerated CML and CML phase of the blast crisis (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); lymphomas including: Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; diffuse intracellular lymphoma (DLBCL), and T-cell lymphoma; multiple myeloma (MM); amyloidosis; Valdenström macroglobulinemia; myelodysplastic syndrome (MDS), including refractory anemia (RA), refractory anemia with annular sideroblasts (RARS), (refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In some embodiments, the cancer is lung cancer, ovarian cancer, colon cancer, or breast cancer. In some embodiments, the cancer is acute myelocytic leukemia. In some embodiments, the cancer is lymphoma.

Depending on the particular disorder or condition to be treated, in some embodiments, the UAE inhibitor of the present invention is administered in conjunction with an additional therapeutic agent or agents. In some embodiments, the additional therapeutic agent (s) is one typically administered to patients with a disorder or condition to be treated. As used herein, additional therapeutic agents typically administered to treat a particular disorder or condition are known to be suitable for the disorder or condition to be treated.

The UAE inhibitor of the present invention can be administered with another therapeutic agent in a unit dosage form or as a separate dosage form. When administered as a separate dosage form, another therapeutic agent can be administered before, during or after the administration of the UAE inhibitor of the present invention.

In some embodiments, the UAE enzyme inhibitor of the present invention is administered in conjunction with a therapeutic agent selected from cytotoxic agents, radiotherapy and immunotherapy, suitable for the treatment of proliferative disorders and cancer. Examples of cytotoxic agents suitable for use in combination with the UAE inhibitors of the present invention include antimetabolites, including, for example, capecitibine, gemcitabine, 5-fluorouracil or 5fluorouracil / leucovorin, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin and methotrex; topoisomerase inhibitors, including, for example, etoposide, teniposide, camptothecin, topotecan, irinotecan, doxorubicin and daunorubicin; vinca alkaloids, including, for example, vincristine and vinblastine; taxanes, including, for example, paclitaxel and docetaxel; platinum agents, including, for example, cisplatin, carboplatin and oxaliplatin; antibiotics, including, for example, actinomycin D, bleomycin, mitomycin C, adriamycin, daunorubicin, idarubicin, doxorubicin and pegylated liposomal doxorubicin; alkylating agents such as melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine and cyclophosphamide; including, for example, CC-5013 and CC-4047; protein tyrosine kinase inhibitors, including, for example, imatinibmesylate and gefitinib; proteasome inhibitors, including, for example, bortezomib; thalidomide and similar analogs; antibodies, including, for example, trastuzumab, rituximab, cetuximab and bevacizumab; mitoxantrone; dexamethasone; prednisone and temozolomide.

Other examples of the inhibitors of the present invention can be combined, including anti-inflammatory drugs, such as corticosteroids, TNF blockers, III RA, azathioprine, cyclophosphamide and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, methotrexate and sulfazalazine; antibacterial and antiviral agents; and agents for the treatment of Alzheimer's disease, such as donepezil, galantamine, memantine and rivastigmine.

In order to fully disclose the present invention, the following preliminary and test examples are provided. These examples are provided for description purposes only and are in no way construed as limiting the scope of the present invention.

Abbreviation Examples and Nomenclature

Compounds synthesized as racemic mixtures are defined as (rac) in the corresponding name. Stereochemical R / S prescriptions were used to determine the relative stereochemistry of the molecules. It is clear that unless otherwise indicated, the compounds are racemic mixtures containing a compound with the named stereochemistry together with its enantiomer. Compounds synthesized as separate enantiomers are defined as (s.e.) - in the corresponding name.

AA - ammonium acetate ACN acetonitrile d - doublet dd - double doublet

DMF - N.N-dimethylformamide

DMSO - dimethyl sulfoxide

EtOAc - Ethyl Acetate

FA - Formic Acid

J - interaction constant hr - hours

Hz - hertz (Hz)

LAH - lithium aluminum hydride

LCMS - liquid chromatography-mass spectrometry

LDA - lithium diisopropylamide m - multiplet

MeOH - methanol s - singlet t- triplet

THF - tetrahydrofuran q - quartet

- 15 035020

Analytical methods

LCMS data were obtained either (i) using an Agilant 1,100 LC (column: Waters Symmetry, 3.5 μm C18 100x4.6 mm) and Waters ZQ MS using the following gradients:

Method using formic acid (FA): composition of the mobile phase A: 99% H ₂ O + 1% ACN [+ 0.1% formic acid]; composition of the mobile phase B: 95% ACN + 5% H ₂ O [+ 0.1% formic acid]. Linear gradient: 5-100% B, 10 min stroke at 1 ml / min.

Ammonium acetate (AA) method: composition of the mobile phase A: 99% H2O + 1% ACN [+ 10 mmol ammonium acetate]; composition of the mobile phase B: 95% ACN + 5% H ₂ O [+ 10 mmol ammonium acetate]. Linear gradient: 5-100% B, 10 minutes stroke at 1 ml / min; or (i) using Agilant 1 100 LC (column: Luna C18 (2) 100A, 150x4.60 mm, 5 μm) and Agilant 1100 LC / MS using the following gradient:

Method using formic acid 2 (FA2): composition of the mobile phase A: 99% H2O + 1% ACN [+ 0.1% formic acid]; composition of the mobile phase B: 95% ACN + 5% H2O [+ 0.1%) formic acid]. Linear gradient: 5-100% B, stroke for 20 minutes at 1 ml / min.

Preparative HPLC was performed using a Phenominex Luna C18 column.

NMR spectra were shown by proton NMR using a 300 MHz Bruker Avance spectrometer equipped with a 5 mm QNP sensor (quadrature nuclear sensor) and a 400 MHz Bruker Avance B spectrometer equipped with a 5 mm QNP sensor for measurements; δ values are expressed in ppm (ppm).

X-ray powder diffraction. XRPD was performed using a Bruker AXS D8 Advance X-ray diffractometer using CuKa radiation (40 kV, 40 mA), an θ-2θ angle meter, and deviations of V4 and receiving slits, a Ge monochromator, and a Lynxeye detector. Tests on the samples were carried out under ambient conditions as samples on a flat plate using powder. The sample was carefully packed in a cavitation mill, and then in a smooth, without interference (510) silicon wafer. The sample was rotated in its own plane throughout the analysis. Data was collected in the range of angles from 2 to 42 ° 2θ, with a step value of 0.05 ° 2θ and a collection time of 0.5 s / step. All collected data was processed using Diffrac Plus XRD Commander v2.6.1 software. Data analysis and presentation were performed using Diffrac Plus EVA v 13.0.0.2 or v 15.0.0.0 software.

Raman spectrum data was collected using a Raman ThermoScientific DXR microscope with the following parameters: laser 780 nm; laser power level 20.0 mW; 780 nm filter; grating 400 lines / nm; a tiny hole in the spectrogram 50 μm; the exposure time is 30 s and the number of exposures 2. The frequency shift range for Raman scattering was in the range from 55.13 to 3411.62 cm ^-1 . OMNIC 8.3 was used as tool management and data analysis software.

Thermal analysis. Thermal phenomena were analyzed using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC data was collected on a Mettler DSC 823E. Typically, 0.5-5.0 mg of a sample in an aluminum pan with tiny holes was heated at 10 ° C 7 1 in from 25 to 300 ° C. A nitrogen purge of the sample was maintained at 50 ml / min above the sample. As software for tool management and data analysis, STARe v9.20 was used. TGA data was collected on a Mettler TGA / SDTA 85 le. Typically, 5-30 mg of the sample was loaded into a pre-weighed aluminum crucible and heated at 10 ° C / min from ambient temperature to 350 ° C. A nitrogen purge of the sample was maintained at 50 ml / min above the sample. As software for tool management and data analysis, STARe v9.20 was used.

Synthetic methods

Example 1a Synthesis of (se) - ((3aR, 4R, 6R, 6aS) -6 - [(2-bromopyrazolo [1,5-a] pyrimidin-7-yl) amino] -2,2dimethyltetrahydro-3aH-cyclopenta [d] [ 1,3] dioxol-4-yl} methanol

Stage 1: (s.e.) - (1R, 2S, 3R, 4R) -1-amino-2,3- (isoproplidenyl) dihydroxy-4-hydroxymethylcyclopentane

To the mixture (se) - (1R, 2S, 3R, 5R) -3-amino-5- (hydroxymethyl) cyclopentane-1,2-dihydrochloride (7.00 g, 38.1 mmol; obtained as a separate enantiomer by the method described in WO 2008/019124) and n-toluenesulfonic acid monohydrate (8.23 g, 43.3 mmol) in methanol (43 ml) was added 2.2 dimethoxypropane (32.3 ml, 263 mmol). The mixture was stirred at room temperature overnight, and then neutralized with 7M NH ₃ / MeOH and concentrated to dryness. The residue was taken up in 2M K ₂ CO ₃ (50 ml) and extracted with EtOAc / CH ₂ CH ₂ 1: 1 (3x50 ml). Mixed Organic

- 16 035020 was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (se) - (1R, 2S, 3R, 4R) -1 amino-2,3- (isoproplidenyl) dihydroxy-4-hydroxymethyl cyclopentane (6.8 g, product yield 95%).

¹ H NMR (400 MHz, DMSO) δ 4.49-4.40 (m, 1H), 4.16-4.05 (m, 1H), 3.44-3.37 (m, 2H), 3 25-3.16 (m, 1H),

2.52-2.42 (m, 1H), 2.16-2.04 (m, 2H), 1.32 (s, 3H), 1.18 (s, 3H).

Step 2: (se) - {(3aR, 4R, 6R, 6aS) -6 - [(2-bromopyrazolo [1,5-a] pyrimidin-7-yl) amino] -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl} methanol

To a suspension of (1R, 2S, 3R, 4R) -1-amino-2,3- (isoproplidenyl) dihydroxy-4-hydroxymethyl cyclopentane (2.76 g, 14.7 mmol) in ethanol (46.5 ml) was added triethylamine (4.28 ml, 30.7 mmol) and 2-bromo-7-chloropyrazolo ^^^ pyrimidine (3.58 g, 15.4 mmol; obtained using the method described by B J. Med. Chem. 2010, 53, 1238 -1249). The reaction mixture was heated at 100 ° C for 3.5 hours, and then cooled to room temperature and concentrated to dryness. The residue was dissolved in chloroform, and then washed with saturated sodium bicarbonate and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The solid was pulverized with diethyl ether and filtered to give (se) - {(3aR, 4R, 6R, 6aS) -6 - [(2bromopyrazolo [1,5-a] pyrimidin-7-yl) amino] -2, 2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4yl} methanol (5.0 g, 88% yield). LCMS: (AA) M + 383;

¹ H NMR (400 MHz, MeOD) δ 8.14 (d, J = 5.6 Hz, 1H), 6.43 (s, 1H), 6.28 (d, J = 5.7 Hz, 1H) 4.64-4.56 (m, 1H); 4.55-4.48 (m, 1H); 4.15-4.05 (m, 1H); 3.75-3.61 (m, 2H), 2.63-2.53 (m, 1H), 2.41-2.31 (m, 1H), 1.88-1.78 (m, 1H), 1.51 (s, 3H) 1.30 (s, 3H).

Example 1b Synthesis of (rac) - {(3aR, 4R, 6R, 6aS) -6 - [(2-bromopyrazolo [1,5-a] pyrimidin-7-yl) amino] -2,2dimethyltetrahydro-3aH-cyclopenta [d] [ 1,3] dioxol-4-yl} methanol

Method applicable for the synthesis of (se) - {(3aR, 4R, 6R, 6aS) -6 - [(2-bromopyrazolo [1,5a] pyrimidin-7-yl) amino] -2,2-dimethyltetrahydro-3aH-cyclopent [d] [1,3] dioxol-4-yl} methanol as a separate enantiomer was carried out to form (race) -rel - {(3aR, 4R, 6R, 6aS) -6 - [(2 bromopyrazolo [1,5-a ] pyrimidin-7-yl) amino] -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4yl} methanol starting from (rac) -rel- (1 R, 2S, 3R, 5R ) -3-amino-5- (hydroxymethyl) cyclopentane-1,2-diol hydrochloride.

Method A.

Example 2

The following procedure describes the synthesis of enantiomerically pure compounds starting from (se) {(3aR, 4R, 6R, 6aS) -6 - [(2-bromopyrazolo [1,5-a] pyrimidin-7-yl) amino] -2,2 -dimethyltetrahydro-3aH-cyclopenta ^] [1,3] dioxol-4-yl} methanol. The same procedure was used for the synthesis of racemic compounds, starting from (race) - {(3aR, 4R, 6R, 6aS) -6 - [(2-bromopyrazolo [1,5-a] pyrimidin-7-yl) amino] - 2,2 dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl} methanol.

Example 2a Synthesis of (se) - ((1H, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin7-yl] amino} cyclopentyl) methyl sulfamate (I-98) cP

SINGLE

0-G daonl n ₂ o

Zia 1

Hg

Zig 2

HjA'SOjCI, DMF

BMNsG (^ G

single enantiomer

Step 1: (se) - ((3aR, 4R, 6R, 6aS) -2,2-dimethyl-6 - {[2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin-7yl] amino} tetrahydro -3aH-cyclopenta [d] [1,3] dioxol-4-yl) methanol

The microwave bottle was filled with {(3aR, 4R, 6R, 6aS) -6 - [(2-bromopyrazolo [1,5a] pyrimidin-7-yl) amino] -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [ 1,3] dioxol-4-yl} methanol (1.50 g, 3.91 mmol), 1-naphthalene boronic acid (1.01 g, 5.87 mmol), [1,1'-bis (diphenylphosphino) ferrocene ] dichloropalladium (P), a complex with dichloromethane (1: 1) (0.160 g, 0.196 mmol), cesium carbonate (2.55 g, 7.83 mmol) and dioxane / water (6: 1, 25 ml). The reaction mixture was heated in a microwave oven at 120 ° C for 90 min, and then cooled to room temperature and concentrated in vacuo. The crude material was purified by column chromatography (eluent: ethyl acetate / hexane) to give (se) - ((3aR, 4R, 6R, 6aS) -2,2-dimethyl-6 - {[2- (1-naphthyl) pyrazolo [ 1,5a] pyrimidin-7-yl] amino} tetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl) methanol (1.5 g, 89% yield). LCMS: (AA) M + 1 431.

- 17 035020

Step 2: (c.e.) - ((1K, 2K, 38.4K) -2,3-dihydroxy-4 - {[2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin-7- yl] amino} cyclopentyl) methyl sulfamate (I-98)

In a vial filled with (se) - ((3aR, 4R, 6R, 6aS) -2,2-dimethyl-6 - {[2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} tetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl) methanol (1.76 g, 4.09 mmol) in K, K-dimethylformamide (7.20 ml), chlorosulfonamide (1 42 g, 12.3 mmol; obtained using the method described in J. Am. Chem. Soc. 2005, 127, 15391). After 1 h, the reaction mixture was quenched with methanol (5 ml). 6.0 M hydrochloric acid in water (3.41 ml, 20.4 mmol) was added and the mixture was stirred for 1 h. The solvent was removed in vacuo and the crude material was purified by preparative HPLC to obtain (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (1naphthyl ^ irazoloPD ^ pyrimidine ^ -yl ^ mino ^ cyclopentyl ^ ethyl sulfamate. LCMS: (AA) M + 1 470;

¹ H NMR (400 MHz, MeOD) δ 8.48-8.40 (m, 1H), 8.19 (d, J = 5.5 Hz, 1H), 7.99-7.90 (m, 2H ), 7.81-7.75 (m, 1H), 7.60-7.47 (m, 3H), 6.69 (s, 1H), 6.37 (d, J = 5.6 Hz, 1H), 4.24-4.06 (m, 3H), 4.04-3.99 (m, 1H), 3.9-3.89 (m, 1H), 2.55-2.45 ( m, 1H), 2.45-2.35 (m, 1H), 1.60-1.48 (m, 1H).

Example 2b-A. Synthesis of (rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclopentyl ) methyl rel-sulfamate (I-2).

The procedure of method A was performed without (rac) - {(3aR, 4R, 6R, 6aS) -6 - [(2-bromopyrazolo [1,5a] pyrimidin-7-yl) amino] -2,2-dimethyltetrahydro-3aH- cyclopenta [d] [1,3] dioxol-4-yl} methanol instead of (se) - {(3aR, 4R, 6R, 6aS) -6 - [(2-bromopyrazolo [1,5-a] pyrimidin-7- il) amino] -2,2-dimethyltetrahydro-3aH cyclopenta ^] [1,3] dioxol-4-yl} methanol. LCMS: (AA) M + 1 470;

¹ H NMR (400 MHz, MeOD) δ 8.48-8.40 (m, 1H), 8.19 (d, J = 5.5 Hz, 1H), 7.99-7.90 (m, 2H ), 7.81-7.75 (m, 1H), 7.60-7.47 (m, 3H), 6.69 (s, 1H), 6.37 (d, J = 5.6 Hz, 1H), 4.24-4.06 (m, 3H), 4.04-3.99 (m, 1H), 3.96-3.89 (m, 1H), 2.55-2.45 ( m, 1H), 2.45-2.35 (m, 1H), 1.60-1.48 (m, 1H).

Method B [Example 2b-B]

Example 2b-B. Alternative synthesis of (race) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (1naphthyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclopentyl) methyl rel-sulfamate (I-2).

Chjcojh

Stage 1: 1-Naphthoyl acetonitrile

To a solution of 2.50 M n-butyllithium in hexane (49.9 ml, 125 mmol) in tetrahydrofuran (49.9 ml), cooled to -78 ° C, acetonitrile (6.52 ml, 125 mmol) was added dropwise. The resulting cloudy mixture was stirred for 30 minutes. Ethyl α-naphthoate (8.87 ml, 49.9 mmol) was added dropwise and the reaction mixture was stirred at -78 ° C for 2 hours. The reaction mixture was warmed to room temperature, sharply cooled with acetic acid (50 ml) and divided into parts between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by column chromatography (eluent: 5-15% CH ₂ Cl ₂ / methanol) to give 1-naphthoylacetonitrile (6.99 g, 72% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.82 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.90 (t, J = 8.1 Hz, 2H), 7.717.64 (m, 1H), 7.57 (dt, J = 15.5, 7.2 Hz, 2H), 4.21 (s, 2H).

Step 2: Ethyl 2- (1-naphthyl) -7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylate

1-Naphthoylacetonitrile (161 mg, 0.825 mmol) and hydrazine (0.11 ml, 3.5 mmol) were heated in ethanol (1.1 ml) at 70 ° C in a closed bottle for 60 hours. The reaction mixture was cooled to room temperature and the solvent was removed. The crude material was taken up in 5 ml of ethyl acetate and washed with water and brine. The organic layer was concentrated in vacuo to give 3- (1-naphthyl) Ш-pyrazol-5-amine, which was dissolved in acetic acid (0.375 ml, 6.60 mmol). Diethylethoxymethylene malonate (0.182 ml, 0.907 mmol) was added and the mixture was heated at 120 ° C for 3 hours in a sealed vial. A precipitate formed during the reaction. The reaction mixture was cooled to room temperature and the solid was collected in a Buchner funnel and washed with pure alcohol for analysis to give ethyl 2- (1-naphthyl) -7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidin-6- carboxylate (166 mg, product yield 60%).

¹ H NMR (300 MHz, DMSO) δ 8.73-8.66 (m, 1H), 8.64 (s, 1H), 8.02 (dd, J = 8.9, 3.4 Hz, 2H ), 7.87-7.78 (m,

- 18 035020

1H), 7.68-7.52 (m, 3H), 6.71 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7 , 1 Hz, 3H).

Step 3: 2- (1-Naphthyl) -7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethyl 2- (1-naphthyl) -7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylate (163 mg, 0.489 mmol) was stirred in 4M NaOH (2.4 ml) and ethanol ( 1.2 ml) at 100 ° C in a closed vial for 5 hours, during which time a precipitate formed. The reaction mixture was diluted with water and a saturated solution of ammonium chloride, adjusting the pH to approximately 4. The precipitate was collected in a Buchner funnel to give 2- (1-naphthyl) -7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidin-6 β-carboxylic acid (145 mg, product yield 97%).

¹ H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 8.72-8.64 (m, 1H), 8.03 (dd, J = 11.4, 5.4 Hz, 2H ), 7.86 (d, J = 6.3 Hz, 1H), 7.69-7.52 (m, 3H), 6.80 (s, 1H).

Step 4: 2- (Naphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one

2- (1-naphthyl) -7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylic acid (2.00 g, 6.55 mmol) was stirred in dimethyl sulfoxide (5.06 ml, 71.2 mol) in a 350 ml closed reaction vessel. Sodium chloride (0.545 g, 9.33 mol) was dissolved in water (2.26 ml) and added to the reaction mixture. The reaction mixture was heated at 150 ° C for 3 days, during which an additional 8 ml of DMSO was added along with 15 ml of additional water. The resulting precipitate was collected in a Buchner funnel to give 2- (naphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (1.48 g, 87%). LCMS: (AA) M + 1 262.

Step 5: 7-Chloro-2- (1-naphthyl) pyrazolo [1,5-a] pyrimidine

2- (Naphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (4.0 g, 15 mmol) was heated in phosphoryl chloride (28 ml) in a closed bottle at 105 ° C and stirred for 5 hours. The crude reaction mixture was cooled to room temperature and slowly poured onto ice. The resulting solid was collected on a Buchner funnel to give 7-chloro-2- (1-naphthyl) pyrazolo [1,5a] pyrimidine (4.3 g, 100% yield). LCMS: (AA) M + 1 280.

Step 6: (race) - (1S, 2R, 3R, 5R) -3- (hydroxymethyl) -5 - {[2- (1-naphthyl) pyrazolo [1,5-a] pyrididin-7yl] amino} cyclopentane- 1,2-diyl reddy-benzoate

A mixture of (rac) - (1R, 2S, 3R, 5R) -3-amino-5- (hydroxymethyl) cyclopeitan-1,2-diyl-reldi-benzoate hydrochloride (0.300 g, 0.767 mmol; obtained as a racemic mixture using the method, described in PCT Publication of Application No. WO 2008/019124), 7-chloro-2- (1-naphthyl) pyrazolo [1,5-a] pyrimidine (0.165 g, 0.590 mmol) and NN-diisopropylethylamine (0.360 ml, 2.06 mmol) in N-methylpyrrolidine (0.80 ml) was heated in a closed reaction vial at 90 ° C and stirred for 2 h.

The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (eluent: 0-60% ethyl acetate / hexanes) to give (race) - (1S, 2R, 3R, 5R) -3- (hydroxymethyl) -5 - {[2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclopentan-1,2-diyl reldi-benzoate (0.086 g, 24% yield). LCMS: (AA) M + 1,599;

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.69-8.57 (m, 1H), 8.29 (d, J = 5.2 Hz, 1H), 8.09-7.98 (m, 2H), 7.97-7.84 (m, 4H), 7.83-7.78 (m, 1H), 7.63-7.32 (m, 10H), 6.82 (s, 1H) 6.34 (d, J = 5.3 Hz, 1H), 5.76-5.66 (m, 1H), 5.65-5.57 (m, 1H), 4.41-4.28 (m, 1H), 3.97-3.84 (m, 1H), 3.80-3.66 (m, 1H), 3.19-3.07 (m, 1H), 2.75-2 59 (m, 2H); 1,921.80 (m, 1H).

Step 7: (rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino } cyclopentyl) methyl rel-sulfamate (I-2)

To a solution of (1S, 2R, 3R, 5R) 3- (hydroxymethyl) -5 - {[2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclopentan-1,2- chloro sulfonamide (141 mg, 1.22 mmol) was added to diyl reldi-benzoate (0.243 g, 0.406 mmol) in Ν, Ν-dimethylformamide (2.4 ml) cooled to 0 ° C. The reaction mixture was stirred for 1 h, and then concentrated in vacuo. Added 1.0 M NaOH (2 ml) and methanol (2 ml) and the reaction mixture was stirred at room temperature until hydrolysis of the benzoate was completed. The reaction mixture was concentrated in vacuo and the residue was suspended in methanol and filtered through a syringe filter. The crude material was purified by column chromatography (eluent: 0-8% MeOH: CH ₂ Cl ₂ ) to give (race) - ((Ш ^^^) - 2,3-dihydroxy-4 - {[2- (1- naphthyl) pyrazolo [1,5a] pyrimidin-7-yl] amino} cyclopentyl) methyl rel-sulfamate (59 mg, product yield 31%). LCMS: (AA) M + 1 470;

¹ H NMR (400 MHz, MeOD) δ 8.48-8.40 (m, 1H), 8.19 (d, J = 5.5 Hz, 1H), 7.99-7.90 (m, 2H ), 7.81-7.75 (m, 1H), 7.60-7.47 (m, 3H), 6.69 (s, 1H), 6.37 (d, J = 5.6 Hz, 1H), 4.24-4.06 (m, 3H), 4.04 -3.99 (m, 1H), 3.96-3.89 (m, 1H), 2.55-2.45 ( m, 1H), 2.45-2.35 (m, 1H), 1.60-1.48 (m, 1H).

Method C [Example 3]

Example 3. Synthesis of ^ e.) - [(III ^^^) - 4 - {[2- (4-chloro-1-naphthyl) pyrazolo [1,5-a] pyrimidin-7yl] amino} -2, 3-dihydroxycyclopentyl] methyl sulfamate (I-108).

- 19 035020

Stage 1: (8..e.) - ((3aK, 4K, 6K, 6a8) -2,2-dimethyl-6 - {[2- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} tetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl) methanol.

To a solution of (se) - {(3aR, 4R, 6R, 6aS) -6 - [(2-bromopyrazolo [1,5-a] pyrimidin-7-yl) amino] -2,2-dimethyltetrahydro-3aH-cyclopent [ d] [1,3] dioxol-4-yl} methanol (500 mg, 1.30 mmol) in 1,4-dioxane (8.0 ml) was added bis (pinacolato) dibor (663 mg, 2.61 mol) , bis (triphenylphosphine) palladium (P) chloride (102 mg, 1.46 mmol) and potassium acetate (630 mg, 6.40 mmol). The mixture was heated at 100 ° C for 20 hours, during which additional bis (triphenylphosphine) palladium (P) chloride (114 mg) was added in two portions. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite to give (se) - ((3aR, 4R, 6R, 6aS) -2,2-dimethyl-6 - {[2- (4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} tetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl) methanol ( 2 g), which was used without further purification.

Step 2: (se) - [(3aR, 4R, 6R, 6aS) -6 - {[2- (4-chloro-1-naphthyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} - 2,2dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl] methanol

The microwave bottle was filled with ((3aR, 4R, 6R, 6aS) -2,2-dimethyl-6 - {[2- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} tetrahydro-3aH-cyclopenta ^] [1,3] dioxol-4-yl) methanol (0.25 g, 0.58 mmol), 1-chloro- 4-iodonaphthalene (0.38 g, 1.30 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (P), in complex with dichloromethane (1: 1) (29 mg, 0.036 mmol), carbonate cesium (0.70 g, 2.2 mmol), 1,4-dioxane (4.0 ml, 50 mmol) and water (0.60 ml, 30 mmol). The reaction mixture was heated in a microwave at 110 ° C for 30 minutes, and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (0-80% ethyl acetate / hexanes) to give (se) [(3aR, 4R, 6R, 6aS) -6 - {[2- (4- [chloro-1-naphthyl) pyrazolo [ 1,5-a] pyrimidin-7-yl] amino} -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl] methanol (0.450 g, product yield 167%). LCMS: (AA) M + 1,465.

Step 3: (se) - [(1R, 2R, 3S, 4R) -4 - {[2- (4-chloro-1-naphthyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} - 2,3-dihydroxycyclopentyl] methyl sulfamate (I-108)

The title compound was synthesized from (se) - [(3aR, 4R, 6R, 6aS) -6 - {[2- (4-chloro-1-naphthyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl] methanol, starting from step 2 of method A. LCMS: (AA) M + 1 504;

¹ H NMR (400 MHz, MeOD) δ 8.54 (d, J = 7.8 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 5.5 Hz, 1H), 7,797.58 (m, 4H), 6.70 (s, 1H), 6.40 (d, J = 5.6 Hz, 1H), 4.26-4.10 (m, 3H), 4.06-3.99 (m, 1H), 3.98-3.91 (m, 1H), 2.56-2.46 (m, 1H), 2.46-2.35 ( m, 1H); 1.61-1.50 (m, 1H).

Method D [Example 4]

Example 4. Synthesis of (rac) - ((1H, 2H ^, 4H) -4- {| 5-chloro-2- (1-naphthyl) 11 andrazolo | 1,5-11111 ^^ 1 ^ 1 ^ 1-7yl] amino} -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-9).

Step 1: 7-hydroxy-2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin-5 (4H) -one

To a solution of 3- (1-naphthyl) -Sh-pyrazol-5-amine (654 mg, 3.12 mmol) and dimethyl malonate (0.394 ml, 3.44 mmol) in anhydrous ethanol (9.44 ml, 162 mmol) was added 0.5 M sodium methoxide in methanol (12.5 ml, 6.25 mmol). The mixture was heated at 120 ° C. under nitrogen overnight. The reaction mixture was cooled to 20 035020 and allowed to reach room temperature, and the solvent was removed in vacuo. The residue was suspended in water and the precipitate was collected in a Buchner funnel to obtain 2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin-7-diol (534 mg, product yield 62%). LCMS: (AA) M + 1 278;

Ή NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.73 (dd, J = 8.2, 4.8 Hz, 1H), 7.99-7.88 (m, 2H) 7.72 (dd,

J = 7.1, 1.1 Hz, 1H), 7.58-7.49 (m, 4H), 5.83 (s, 1H), 4.14 (s, 1H).

Step 2: 5,7-dichloro-2- (1-naphthyl) pyrazolo [1,5-a] pyrimidine.

A mixture of 7-hydroxy-2- (1-naphthyl) pyrazolo [1,5-a] pyrimidin-5 (4H) -one (534 mg, 1.92 mmol), N, N diethylaniline (0.952 ml, 5.98 mmol) , phosphorus pentachloride (205 mg, 0.986 mmol) and phosphoryl chloride (8.98 ml, 96.3 mmol) were stirred at 120 ° C for 20 hours. The reaction mixture was cooled to room temperature and poured onto ice. The precipitate was collected in a Buchner funnel to give 5,7-dichloro-2 (1-naphthyl) pyrazolo [1.5 g] pyrimidine (538 mg, 89% yield). LCMS: (AA) M + 1 314;

¹ H NMR (400 MHz, DMSO) δ 8.68-8.61 (m, 1H), 8.09-8.02 (m, 2H), 7.90 (dd, J = 7.2, 1, 2 Hz, 1H), 7.72 (s, 1H), 7.65 (dd, J = 8.2, 7.2 Hz, 1H), 7.63-7.58 (m, 2H), 7, 32 (s, 1H).

Step 3: (race) - (1R, 2S, 3R, 5R) -3 - {[5-chloro-2- (1-naphthyl) pyrazolo [1,5-a] pyridin-7-yl] amino} -5 (hydroxy methyl) cyclopentane-1,2-diyl rel-dibenzoate

Suspension (rac) - (1R, 2S, 3R, 5R) -3-amino-5- (hydroxymethyl) cyclopentane-1,2-diyl reldi-benzoate hydrochloride (150 mg, 0.382 mmol), 5.7-dichloro-2 - (1-naphthyl) pyrazolo [1,5-a] pyrimidine (100 mg, 0.318 mmol) and ^^ diisopropylethylamine (0.166 ml, 0.955 mmol) in tetrahydrofuran (1.05 ml) were heated in a closed reaction vial at 80 ° C for 2.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The crude material was purified by column chromatography (eluent: 0-80% ethyl acetate: hexanes) to give (rac) - (1R, 2S, 3R, 5R) -3 - {[5-chloro-2 (Lnaphthyl ^ irazolo ^ E ^ pyrimidine ^ -yl ^ mino ^ Dhydroxymethyl ^ iclopentane ND-diyl reldi-benzoate (118 mg, product yield 59%). LCMS: (AA) M + 1 633;

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57-8.52 (m, 1H), 8.01-7.97 (m, 2H), 7.94-7.89 (m, 2H), 7.88-7.83 (m, 2H), 7.73 (dd, J = 7.1, 1.1 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7 58-7.49 (m, 2H), 7.48-7.32 (m, 8H), 6.71 (s, 1H), 6.33 (s, 1H), 5.66 (t, J = 4.8 Hz, 1H), 5.55 (t, J = 5.0 Hz, 1H), 4.27-4.18 (m, 1H), 3.85-3.79 (m, 1H) 3.59-3.52 (m, 1H); 2.57-2.49 (m, 2H); 1.77-1.64 (m, 1H).

Step 4: (rac) - ((^^^^) - 4 - {[5-chloro-2- (1-naphthyl) pyrazolo [1,5sh] pyrimidin-7-yl] amino} -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-9)

The title compound was synthesized from (rac) - (1R, 2S, 3R, 5R) -3 - {[5-chloro-2- (1-naphthyl) pyrazolo [1,5a] pyrimidin-7-yl] amino} -5- (hydroxymethyl) cyclopentane-1,2-diyl rel-dibenzoate starting from step 7 of method B (product yield 19%). LCMS: (AA) M + 1 504;

¹ H NMR (400 MHz, MeOD) δ 8.48-8.42 (m, 1H), 7.99-7.91 (m, 2H), 7.81-7.76 (m, 1H), 7 , 61-7.50 (m, 3H), 6.65 (s, 1H), 6.43 (s, 1H), 4.25-4.06 (m, 3H), 4.01 (t, J = 6.0 Hz, 1H), 3.94 (t, J = 5.3 Hz, 1H), 2.54-2.34 (m, 2H), 1.57 (dt, J = 12.6, 9.0 Hz, 1H).

Method E [Example 5]

Example 5. Synthesis of (rac) - {(^^^^) - 2,3-dihydroxy-4 - [(5-methyl-2-phenylpyrazolo [1,5sc] pyrimidin-7-yl) amino] cyclopentyl} methyl rel Sulfamate (I-4).

Step 1: 5-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-7 (4H) -one

A mixture of 5-phenyl-III-pyrazol-3-ylamine (501 mg, 3.15 mmol) and ethyl 3-oxobutanoic acid ester (0.433 ml, 3.39 mmol) in anhydrous toluene (2.9 ml) was heated at 120 ° C in a closed bottle. After 2 hours, the reaction mixture was cooled to room temperature. The precipitate was collected in a Buchner funnel and washed with hexanes to give 5-methyl-2-phenylpyrazolo [1.5 g] pyrimidine 7 (4 ^^^ (577 mg, 81% yield). LCMS: (AA) M + 1 226;

¹ H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 8.01-7.92 (m, 2H), 7.49-7.43 (m, 2H), 7.42-7 37 (m, 1H); 6.57 (s, 1H); 5.60 (s, 1H); 2.29 (s, 3H).

Step 2: 7-chloro-5-methyl-2-phenylpyrazolo [1,5-a] pyrimidine

5-Methyl-2-phenylpyrazolo [1,5-a] pyrimidin-7 (4H) -one (210 mg, 0.932 mmol) was heated in phosphoryl chloride (1.74 ml, 18.6 mmol) in a closed bottle at 100 ° C for 2 hours. The reaction mixture was cooled to room temperature and slowly poured onto ice. The resulting suspension was extracted with dichloromethane and washed with brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by night chromatography (eluent 0-100% ethyl acetate: hexanes) to give 7-chloro-5-methyl-2-phenylpyrazolo [1,5-a] pyrimidine (123 mg, 54% yield). LCMS: (AA) M + 1 244;

¹ H NMR (400 MHz, DMSO) δ 8.07-8.02 (m, 2H), 7.53-7.47 (m, 2H), 7.46-7.41 (m, 1H), 7 32 (s, 1H); 7.23 (s, 1H); 2.53 (s, 3H).

Step 3: (rac) - (1S, 2R, 3R, 5R) 3- (hydroxymethyl) -5 - [(5-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-7yl) amino] cyclopentane-1, 2-diyl reddy-benzoate

The title compound was synthesized from 7-chloro-5-methyl-2-phenylpyrazolo [1,5-a] pyrimidine starting from step 3 of method D, except for using DMF instead of THF. LCMS: (AA) M + 1,563;

¹ H NMR (400 MHz, MeOD) δ 8.06-7.97 (m, 3H), 7.88 (d, J = 7.7 Hz, 2H), 7.62-7.49 (m, 2H ), 7.46-7.29 (m, 8H), 6.62 (s, 1H), 6.24 (s, 1H), 5.70-5.58 (m, 2H), 4.60- 4.50 (m, 1H), 3.91-3.81 (m, 1H), 3.80-3.72 (m, 1H), 2.78-2.65 (m, 2H), 2, 34 (s, 3H), 1.95-1.82 (m, 1H).

Step 4: (rac) - {(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - [(5-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-7yl) amino] cyclopentyl} methyl rel-sulfamate (I-4)

The title compound was synthesized from (rac) - (1S, 2R, 3R, 5R) -3- (hydroxymethyl) -5 - [(5-methyl-2phenylpyrazolo [1,5-a] pyrimidin-7-yl) amino] cyclopentane- 1,2-diyl reldi-benzoate, starting from step 7 of method B (product yield 35%). LCMS: (AA) M + 1 434;

¹ H NMR (400 MHz, MeOD) δ 8.00 (d, J = 7.4 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 6.63 (s, 1H), 6.21 (s, 1H), 4.28-4.17 (m, 2H), 4.12-4.04 (m, 1H ), 4.03-3.95 (m, 2H), 2.58-2.36 (m, 5H), 1.62-1.50 (m, 1H).

Method F [Example 6]

Example 6. Synthesis of (race) - {(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - [(6-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-7-yl) amino ] cyclopentyl} methyl rel-sulfamate (I-89).

Step 1: 7-hydroxy-6-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-5 (4H) -one

To a solution of dimethyl methyl malonate (1.30 ml, 9.80 mmol) and 5-amino-3-phenylpyrazole (1.50 g, 9.42 mmol) in methanol (11 ml) was added 25% sodium methoxide in methanol (6, 04 ml, 26.4 mmol). The reaction mixture was heated at 75 ° C for 48 hours. The precipitate was collected in a Buchner funnel and washed with dichloromethane to give 7-hydroxy-6-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-5 (4H) -one (2 , 87 g, product yield 95%). LCMS: (AA) M + 1 242;

¹ H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 7.92-7.86 (m, 2H), 7.41-7.33 (m, 2H), 7.32-7 26 (m, 1H); 5.92 (s, 1H); 1.75 (s, 3H).

Stage 2: 5,7-dichloro-6-methyl-2-phenylpyrazolo [1,5-a] pyrimidine

The title compound was synthesized from 7-hydroxy-6-methyl-2-phenylpyrazolo [1,5-a] pyrimidin5 (4H) -one, starting from step 2 of method D (yield 61%).

Step 3: (race) - (1R, 2S, 3R, 5R) -3 - [(5-chloro-6-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-7-yl) amino] -5 ( hydroxymethyl) cyclopentane-1,2-diyl reddy-benzoate

The title compound was synthesized from 5,7-dichloro-6-methyl-2-phenylpyrazolo [1,5-a] pyrimidine starting from step 3 of method D, except for using DMF instead of THF (85% yield). LCMS: (AA) M + 1,597.

Step 4: (race) - {(1R, 2R, 3S, 4R) -4 - [(5-chloro-6-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-7-yl) amino] -

2,3-dihydroxycyclopentyl} methyl rel-sulfamate

The title compound was synthesized from (rac) - (1B ^, 3B, 5B) -3 - [(5-chloro-6-methyl-2 phenylpyrazolo [1,5-a] pyrimidin-7-yl) amino] -5- (hydroxymethyl ) cyclopentane-1,2-diyl reldi-benzoate, starting from step 7 of method B (product yield 74%). LCMS: (AA) M + 1,468.

Step 5: (race) - {(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - [(6-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-7yl) amino] cyclopentyl} methyl rel-sulfamate (I-89)

The pressure vessel was filled with (rac) - {(1B, 2B ^, 4B) -4 - [(5-chloro-6-methyl-2 phenylpyrazolo [1,5-a] pyrimidin-7-yl) amino] -2 , 3-dihydroxycyclopentyl} methyl rel-sulfamate (111 mg, 0.237 mmol), tetrahydrofuran (1.4 ml) and Pd [10% on carbon / 50%, wettable with water; type Degussa) 76 mg, 0.036 mmol)]. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (30 psi) for 18 hours. The reaction mixture was filtered through celite and concentrated in vacuo. The crude material was purified by preparative HPLC to give (race) - {(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - [(6-methyl-2-phenylpyrazolo [1,5-a] pyrimidine- 7-yl) amino] cyclo-22 035020 lopentyl} methyl rel-sulfamate (15 mg, product yield 13%). LCMS: (FA) M + 1 434;

¹ H NMR (400 MHz, MeOD) δ 8.05-7.98 (m, 2H), 7.94 (s, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7, 36 (t, J = 7.3 Hz,

1H), 6.69 (s, 1H), 4.20 (t, J = 7.8 Hz, 2H), 4.03-3.94 (m, 2H), 2.64 (s, 1H), 2.54-2.31 (m, 5H); 1.64-1.51 (m, 1H).

Example 7. Compounds obtained using method A (rac) - [(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (1H-indol-3-yl) pyrazolo [1, 5-a] pyrimidin-7-yl] amino} cyclopentyl] methyl rel-sulfamate (I-32). The title compound was prepared using {1 [tert-butyl (dimethyl) silyl] -S-indol-3-yl} boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,459;

¹ H NMR (400 MHz, MeOD) δ 8.31-8.26 (m, 1H), 8, 10 (d, J = 5.5 Hz, 1H), 7.86 (s, 1H), 7, 46-7.40 (m, 1H), 7.22-7, 14 (m, 2H), 6.70 (s, 1H), 6.28 (d, J = 5.6 Hz, 1H), 4 , 29-4.19 (m, 2H), 4, 17-4.09 (m, 1H), 4.07 (t, J = 5.8 Hz, 1H), 4.00 (t, J = 5 4 Hz, 1H), 2.61-2.50 (m, 1H), 2.48-2.37 (m, 1H), 1.67-1.56 (m, 1H).

(rac) - [(1R, 2R, 3S, 4R) -4 - {[2- (9H-carbazol-3-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2.3 -dihydroxycyclopentyl] methyl rel-sulfamate (I-37). The title compound was prepared using 3 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -9H-carbazole in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1 509;

¹ H NMR (400 MHz, MeOD) δ 8.78 (s, 1H), 8.19-8.03 (m, 3H), 7.51 (d, J = 8.5 Hz, 1H), 7, 46 (d, J = 8.1 Hz, 1H), 7.38 (dd, J = 8.1, 7.1 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 6.82 (s, 1H), 6.29 (d, J = 5.5 Hz, 1H), 4.31-4.20 (m, 2H), 4.16-3.97 (m, 3H) 2.61-2.49 (m, 1H); 2.49-2.37 (m, 1H); 1.68-1.55 (m, 1H).

(rac) - [(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (5-methyl-2-phenyl-1,3-thiazol-4-yl) pyrazolo [1, 5-a] pyrimidin-7-yl] amino} cyclopentyl] methyl rel-sulfamate (I-38).

The title compound was prepared using 5-methyl-2-phenyl-4- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) -1,3-thiazole in step 1 instead of 1-naphthalenboronic acid . LCMS: (AA) M + 1 517;

¹ H NMR (300 MHz, MeOD) δ 8.17 (d, J = 5.5 Hz, 1H), 8.06-7.93 (m, 2H), 7.56-7.41 (m, 3H ), 6.83 (s, 1H), 6.36 (d, J = 5.5 Hz, 1H), 4.34-3.95 (m, 5H), 2.84 (s, 3H), 2 73-2.34 (m, 2H); 1.70-1.53 (m, 1H).

(rac) - [(1R, 2R, 3S, 4R) -4 - {[2- (5-chloro-1H-indol-3-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2,3-dihydroxycyclopentyl] methyl rel-sulfamate (I-54). The title compound was prepared using 1-side-5-chloroindole-3-boronic acid pinacol ester in step 1 instead of 1 naphthalene boronic acid. LCMS: (AA) M + 1,493;

¹ H NMR (300 MHz, MeOD) δ 8.28 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 5.5 Hz, 1H), 7.91 (s, 1H) , 7.41 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 10.6 Hz, 1H), 6.68 (s, 1H), 6.28 (d, J = 5.5 Hz, 1H), 4.32-3.94 (m, 5H), 2.62-2.34 (m, 2H), 1.68-1.48 (m, 1H).

(rac) - [(1R, 2R, 3S, 4R) -4 - {[2- (6-chloro-1H-indol-3-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2,3-dihydroxycyclopentyl] methyl rel-sulfamate (I-55). The title compound was prepared using 1-side-6-chloroindole-3-boronic acid pinacol ester in step 1 instead of 1 naphthalene boronic acid. LCMS: (AA) M + 1,493;

¹ H NMR (300 MHz, MeOD) δ 8.30 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.87 (s, 1H) 7.44 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 6.67 (s, 1H), 6.25 (d, J = 5.5 Hz, 1H) 4.31-4.18 (m, 2H); 4.17-3.95 (m, 3H); 2.60-2.36 (m, 2H); 1.66-1.50 (m, 1H).

(rac) - [(1R, 2R, 3S, 4R) -4 - {[2- (9H-carbazol-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2.3 -dihydroxycyclopentyl] methyl rel-sulfamate (I-62). The title compound was prepared using 2 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -9H-carbazole in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1 509;

¹ H NMR (400 MHz, MeOD) δ 8.14-8.03 (m, 4H), 7.88-7.83 (m, 1H), 7.46 (d, J = 8.1 Hz, 1H ), 7.41-7.34 (m, 1H), 7.20-7.13 (m, 1H), 6.82 (s, 1H), 6.28 (d, J = 5.6 Hz, 1H), 4.29-4.19 (m, 2H), 4.15-3.97 (m, 3H), 2.58-2.48 (m, 1H), 2.48-2.36 ( m, 1H); 1.65-1.54 (m, 1H).

(rac) - [(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (2-phenyl-1,3-oxazol-5-yl) pyrazolo [1,5-a] pyrimidin-7yl] amino} cyclopentyl] methyl rel-sulfamate (I-67).

The title compound was prepared using 2-phenyl-5- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) oxazole in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1,487;

¹ H NMR (300 MHz, MeOD) δ 8.22-8.09 (m, 3H), 7.80 (s, 1H), 7.59-7.51 (m, 3H), 6.81 (s , 1H), 6.39 (d, J = 5.6 Hz, 1H), 4.31-4.19 (m, 2H), 4.18-4.08 (m, 1H), 4.07- 3.96 (m, 2H); 2.57-2.37 (m, 2H); 1.67-1.56 (m, 1H).

(se) - [(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ({2- [2-methoxy-5- (trifluoromethoxy) phenyl] pyrazolo [1,5a] pyrimidin-7-yl } amino) cyclopentyl] methyl sulfamate (I-102). The title compound was prepared using 2-methoxy-5- (trifluoromethoxy) phenylboronic acid in step 1 instead of 1 naphthalenboronic acid. LCMS: (AA) M + 1,534;

¹ H NMR (400 MHz, DMSO) δ 8.22 (d, J = 3.1 Hz, 1H), 8.16 (d, J = 5.3 Hz, 1H), 7.75 (s, 1H) 7.56-7.33 (m, 3H), 7.27 (d, J = 9.2 Hz, 1H), 6.97 (s, 1H), 6.29 (d, J = 5.4 Hz, 1H), 5.04 (d, J = 5.4 Hz, 1H), 4.82 (s, 1H), 4.17-4.00 (m, 2H), 4.00-3.94 (m, 2H), 3.81-3.73 (m, 1H), 3.32 (s, 3H), 2.38-2.18 (m, 2H), 1.57-1.45 (m , 1H).

(rac) - ((III ^^^) - 4- (2- (dibenzo [b] furan-4-yl) pyrazolo [1,5-a] pyrimidin-7 -amino) -2,3-dihydroxycyclopentyl) methyl rel- sulfamate (I-10). The title compound was prepared using dibenzothiophene-4-boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA)

- 23 035020

M + 1,510;

¹ H NMR (400 MHz, MeOD) δ 8.40-8.34 (m, 1H), 8.18 (d, J = 5.5 Hz, 1H), 8.10-8.04 (m, 2H ), 7.72 (d, J = 8.2 Hz, 1H), 7.58-7.37 (m, 3H), 7.31 (s, 1H), 6.37 (d, J = 5, 6 Hz, 1H), 4.30-4.21 (m, 2H), 4.19-4.11 (m, 1H), 4.104.05 (m, 1H), 4.03-3.99 (m , 1H), 2.62-2.50 (m, 1H), 2.49-2.38 (m, 1H), 1.69-1.57 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -4- (2- (dibenzo [b, d] furan-4-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2, 3-dihydroxycyclopentyl) methyl sulfamate (I-103). The title compound was prepared using dibenzothiophene-4-boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,510;

¹ H NMR (400 MHz, MeOD) δ 8.40-8.34 (m, 1H), 8.18 (d, J = 5.5 Hz, 1H), 8.10-8.04 (m, 2H ), 7.72 (d, J = 8.2 Hz, 1H), 7.58-7.37 (m, 3H), 7.31 (s, 1H), 6.37 (d, J = 5, 6 Hz, 1H), 4.30-4.21 (m, 2H), 4.19-4.1 1 (m, 1H), 4.104.05 (m, 1H), 4.03-3.99 ( m, 1H), 2.62-2.50 (m, 1H), 2.49-2.38 (m, 1H), 1.69-1.57 (m, 1H).

(rac) - [(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (1H-indol-5-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclopentyl] methyl rel-sulfamate (I-74). The title compound was prepared using 5indolyl-boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,459;

¹ H NMR (300 MHz, MeOD) δ 8.29 (s, 1H), 8.18 (d, J = 7.0 Hz, 1H), 7.93-7.76 (m, 1H), 7, 48 (d, J = 8.5 Hz, 1H), 7.35-7.25 (m, 1H), 6.89 (s, 1H), 6.61 (d, J = 7.1 Hz, 1H ), 6.57-6.53 (m, 1H), 4.44-4.18 (m, 3H), 4.17-4.10 (m, 1H), 4.04-3.98 (m , 1H); 2.54-2.35 (m, 2H); 1.82-1.63 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidine-7ylamino) cyclopentyl) methyl sulfamate (I-101).

The title compound was prepared using trifluoromethylthio-3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzene in step 1 instead of 1 naphthalenboronic acid. LCMS: (AA) M + 1,520;

¹ H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 5.4 Hz, 1H) , 7.71 (d, J = 7.8 Hz, 1H), 7.65-7.54 (m, 1H), 6.83 (s, 1H), 6.34 (d, J = 5.5 Hz, 1H), 4.30-3.92 (m, 5H), 2.57-2.34 (m, 2H), 1.671.52 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl) methyl rel sulphamate (I-44).

The title compound was prepared using trifluoromethylthio-3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzene in step 1 instead of 1 naphthalenboronic acid. LCMS: (AA) M + 1,520;

¹ H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 5.4 Hz, 1H) , 7.71 (d, J = 7.8 Hz, 1H), 7.65-7.54 (m, 1H), 6.83 (s, 1H), 6.34 (d, J = 5.5 Hz, 1H), 4.30-3.92 (m, 5H), 2.57-2.34 (m, 2H), 1.671.52 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -4- (2- (4-fluoronaphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl sulfamate ( I-100). The title compound was prepared using 4 fluoronaphthalene-1-boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,488;

¹ H NMR (400 MHz, MeOD) δ 8.60-8.49 (m, 1H), 8.27-8.14 (m, 2H), 7.85-7.77 (m, 1H), 7 70-7.61 (m, 2H),

7.37-7.26 (m, 1H), 6.71 (s, 1H), 6.42 (d, J = 5.6 Hz, 1H), 4.28-4.12 (m, 3H) 4.08-4.03 (m, 1H), 4.01-3.96 (m, 1H), 2.62-2.36 (m, 2H), 1.65-1.51 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((2- (2-methoxy-5- (trifluoromethyl) phenyl) pyrazolo [1,5-a] pyrimidin-7 -yl) amino) cyclopentyl) methyl rel-sulfamate (I-65).

The title compound was prepared using 2-methoxy-5- (trifluoromethyl) phenylboronic acid in step 1 instead of 1-naphthalenboronic acid. LCMS: (FA) M + 1 518;

¹ H NMR (400 MHz, DMSO) δ 8.59-8.45 (m, 1H), 8.16 (d, J = 5.3 Hz, 1H), 7.91-7.70 (m, 2H ), 7.60-7.30 (m, 3H), 6.97 (s, 1H), 6.29 (d, J = 5.4 Hz, 1H), 5.05 (s, 1H), 4 82 (s, 1H), 4.22-4.07 (m, 1H), 4.07-3.89 (m, 5H), 3.813.69 (m, 1H), 2.37-2.16 (m, 2H); 1.59-1.44 (m, 1H).

(rac) - ((^^^^) - 2,3-dihydroxy-4 - ((2- (2-methoxy-5- (trifluoromethoxy) phenyl) pyrazolo [1,5i] pyrimidin-7-yl) amino) cyclopentyl) methyl rel-sulfamate (I-66).

The title compound was prepared using 2-methoxy-5- (trifluoromethoxy) phenylboronic acid in step 1 instead of 1-naphthalenboronic acid. LCMS: (FA) M + 1,534;

¹ H NMR (400 MHz, DMSO) δ 8.22 (d, J = 3.0 Hz, 1H), 8.15 (d, J = 5.3 Hz, 1H), 7.44-7.37 ( m, 1H), 7.29-7.23 (m, 1H), 6.97 (s, 1H), 6.28 (d, J = 5.4 Hz, 1H), 4.16-4.08 (m, 1H), 4.05-3.89 (m, 6H), 3.80-3.71 (m, 1H), 2.372.17 (m, 2H), 1.57-1.43 (m , 1H).

(rac) - ((1R, 2R, 3S, 4R) -4 - ((2- (benzo [b] thiophen-4-yl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) -2 , 3-dihydroxycyclopentyl) methyl rel-sulfamate (I-61).

The title compound was prepared using benzothiophene-4boronic acid pinacol ester in step 1 instead of 1-naphthaleneboronic acid. LCMS: (FA) M + 1,476;

¹ H NMR (400 MHz, DMSO) δ 8.38 (d, J = 5.5 Hz, 1H), 8.20-8.15 (m, 2H), 8.07 (d, J = 8.0 Hz, 1H), 7.95-7.91 (m, 1H), 7.87 (d, J = 5.6 Hz, 1H), 7.77 -7.69 (m, 1H), 7.58 -7.41 (m, 2H), 6.93 (s, 1H), 6.31 (d, J = 5.4 Hz, 1H), 4.17-4.09 (m, 1H), 4, 07-3.93 (m, 4H), 3.81-3.74 (m, 2H), 2.41 -2.18 (m, 2H), 1.61-1.43 (m, 1H).

- 24 035020 (rac) - ((1K, 2K, 38.4K) -2,3-dihydroxy-4 - ((2- (5- (trifluoromethyl) thiophen-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) cyclopentyl) methyl rel-sulfamate (I-60).

The title compound was prepared using 5- (trifluoromethyl) thiophen-2-ylboronic acid in step 1 instead of 1-naphthalenboronic acid. LCMS: (FA) M + 1,494;

¹ H NMR (400 MHz, DMSO) δ 8.21-8.13 (m, 1H), 7.82-7.75 (m, 2H), 7.74-7.67 (m, 1H), 7 48 (s, 2H), 6.98 (s, 1H), 6.31 (d, J = 5.5 Hz, 1H), 5.06-5.00 (m, 1H), 4.84- 4.77 (m, 1H), 4.17-4.07 (m, 1H), 4.06-3.89 (m, 3H),

3.80-3.71 (m, 1H), 2.37-2.17 (m, 2H), 1.53-1.42 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4 - ((2- (dibenzo [b, d] thiophen-4-yl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-56).

The title compound was prepared using dibenzo [B] thiophen-4-ylboronic acid in step 1 instead of 1-naphthalenboronic acid. LCMS: (FA) M + 1 526;

¹ H NMR (300 MHz, DMSO) δ 8.51-8.39 (m, 2H), 8.27-8.20 (m, 2H), 8.12-8.02 (m, 1H), 7 67 (t, J = 7.7 Hz, 1H), 7.61-7.42 (m, 4H), 7.39-7.27 (m, 1H), 7.13 (s, 1H), 6.39 (d, J = 5.4 Hz, 1H), 4.21-4.13 (m, 1H), 4.1 1-3.97 (m, 3H), 3.86-3.76 (m, 1H), 2.46-2.36 (m, 1H), 2.36-2.21 (m, 1H), 1.68-1.42 (m, 1H).

(rac) - ((^^^^) - 4 - ((2- (3- (difluoromethoxy) phenyl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) -2,3-dihydroxycyclopentyl) methyl rel- sulfamate (I-50).

The title compound was prepared using 3- (difluoromethoxy) benzene boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,486;

¹ H NMR (300 MHz, DMSO) δ 8.15 (d, J = 5.3 Hz, 1H), 8.00-7.93 (m, 1H), 7.92-7.87 (m, 1H ), 7.77-7.66 (m, 1H), 7.58-7.49 (m, 2H), 7.25-7.18 (m, 1H), 6.97 (s, 1H), 6.28 (d, J = 5.4 Hz, 1H), 5.12-4.94 (m, 1H), 4.90-4.72 (m, 1H), 4.18-4.09 ( m, 1H), 4.08-3.89 (m, 3H), 3.82-3.72 (m, 1H), 2.40-2.17 (m, 2H), 1.57-1, 40 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((2- (3-phenoxyphenyl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) cyclopentyl) methyl rel-sulfamate (I-51).

The title compound was prepared using 4,4,5,5-tetramethyl-2- (3-phenoxyphenyl) -1,3,2 dioxaborolan in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1 512;

¹ H NMR (300 MHz, DMSO) δ 8.13 (d, J = 5.3 Hz, 1H), 7.92-7.82 (m, 2H), 7.49 (t, J = 7.9 Hz, 1H), 7.44-7.35 (m, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.08-6.97 (m, 3H), 6.93 (s, 1H), 6.26 (d, J = 5.4 Hz, 1H), 4.20-4.07 (m, 1H), 4.073.86 (m, 3H), 3.80-3, 69 (m, 1H), 2.40-2.14 (m, 2H), 1.55-1.40 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4 - ((2- (benzo [b] thiophen-7-yl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) -2 , 3-dihydroxycyclopentyl) methyl rel-sulfamate (I-45).

The title compound was prepared using 1-benzothien-7-ylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (FA) M + 1 476;

¹ H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.10 (d, J = 7.3 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H) 7.88 (d, J = 5.5 Hz, 1H), 7.59-7.46 (m, 4H), 7.26 (d, J = 7.5 Hz, 1H), 7.10 ( s, 1H), 6.39 (d, J = 5.2 Hz, 1H), 5.09 (d, J = 5.6 Hz, 1H), 4.85 (d, J = 5.3 Hz, 1H), 4.23-4.12 (m, 1H), 4.11-3.95 (m, 3H), 3.86-3.76 (m, 1H), 2.48-2.37 ( m, 1H), 2.36-2.24 (m, 1H), 1.56-1.44 (m, 1H).

(rac) - ((^^^^) - 2,3-dihydroxy-4 - ((2- (3- (trifluoromethoxy) phenyl) pyrazolo [1,5-a] pyrimidin-7yl) amino) cyclopentyl) methyl rel Sulfamate (I-40).

The title compound was prepared using m- (trifluoromethoxy) phenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 504;

¹ H NMR (300 MHz, DMSO) δ 8.20-8.04 (m, 3H), 7.67-7.58 (m, 1H), 7.44-7.36 (m, 1H), 7 03 (s, 1H), 6.29 (d, J = 5.4 Hz, 1H), 5.04 (s, 1H), 4.82 (s, 1H), 4.18-4.08 ( m, 1H), 4.08-3.89 (m, 3H), 3.82-3.72 (m, 1H), 2.39-2.17 (m, 2H), 1.58-1, 42 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((2- (3- (pyridin-2-yl) phenyl) pyrazolo [1,5-a] pyrimidin-7yl ) amino) cyclopentyl) methyl rel-sulfamate (I-36). The title compound was prepared using (3-pyridin-2-yl-phenyl) boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,497;

¹ H NMR (300 MHz, DMSO) δ 8.79-8.66 (m, 2H), 8.22-7.87 (m, 6H), 7.80-7.67 (m, 1H), 7 66-7.56 (m, 1H), 7.45-7.36 (m, 1H), 7.02 (s, 1H), 6.28 (d, J = 5.3 Hz, 1H), 4.20-3.95 (m, 4H), 3.82-3.74 (m, 1H), 3.40-3.34 (m, 1H), 2.42-2.19 (m, 2H) ), 1.60-1.44 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4 - ((2- (3-bromophenyl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-28). The title compound was prepared using 3-bromophenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,498;

¹ H NMR (300 MHz, DMSO) δ 8.33 (s, 1H), 8.15 (d, J = 5.3 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H) 7.78-7.71 (m, 1H), 7.63-7.57 (m, 1H), 7.51-7.40 (m, 3H), 6.99 (s, 1H), 6 , 28 (d, J = 5.4 Hz, 1H), 5.05-4.99 (m, 1H), 4.83-4.77 (m, 1H), 4.18-4.09 (m , 1H), 4.07-3.91 (m, 3H), 3.81-3.73 (m, 1H), 2.40-2.17 (m, 2H), 1.58-1.43 (m, 1H).

(rac) - ((^^^^) - 4 - ((2- (2-fluoro-5- (trifluoromethyl) phenyl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) -

2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-29).

The title compound was prepared using 2-fluoro-5- (trifluoromethyl) phenylboronic acid in step 1 instead of 1-naphthalenboronic acid. LCMS: (FA) M + 1 506;

¹ H NMR (400 MHz, DMSO) δ 8.64-8.58 (m, 1H), 8.20 (d, J = 5.3 Hz, 1H), 7.94-7.84 (m, 2H ), 7.67-7.59 (m, 1H), 7.48 (s, 2H), 6.86 (d, J = 4.2 Hz, 1H), 6.35 (d, J = 5, 4 Hz, 1H), 5.04 (d, J = 5.6 Hz, 1H), 4.81 (d, J = 5.2 Hz, 1H),

- 25 035020

4.17-4.08 (m, 1H), 4.07-3.92 (m, 3H), 3.81-3.73 (m, 1H), 2.38-2.17 (m, 2H) ), 1.58-1.45 (m, 1H).

(rac) - ((1K, 2K, 38.4K) -4 - ((2- (2-chloro-5- (trifluoromethyl) phenyl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) 2 , 3-dihydroxycyclopentyl) methyl rel-sulfamate (I-30).

The title compound was prepared using 2-chloro-5- (trifluoromethyl) phenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (FA) M + 1,522;

¹ H NMR (400 MHz, DMSO) δ 8.33-8.27 (m, 1H), 8.21 (d, J = 5.3 Hz, 1H), 7.95-7.91 (m, 1H ), 7.90-7.81 (m, 2H), 7.47 (s, 2H), 6.95 (s, 1H), 6.34 (d, J = 5.4 Hz, 1H), 5 02 (d, J = 5.5 Hz, 1H), 4.80 (d, J = 5.2 Hz, 1H), 4.17-4.06 (m, 1H), 4.06-3, 90 (m, 3H), 3.80-3.71 (m, 1H), 2.38-2.15 (m, 2H), 1.57-1.43 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((2- (quinolin-8-yl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) cyclopentyl) methyl rel-sulfamate (I-17). The title compound was prepared using 8-quinoline-boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (FA) M + 1 471;

¹ H NMR (400 MHz, DMSO) δ 9.07-9.01 (m, 1H), 8.66-8.60 (m, 1H), 8.49-8.43 (m, 1H), 8 , 18 (d, J = 5.3 Hz, 1H), 8.10-8.03 (m, 1H), 7.79-7.70 (m, 2H), 7.65-7.57 (m , 1H), 7.48 (s, 3H), 6.28 (d, J = 5.3 Hz, 1H), 5.04 (d, J = 5.5 Hz, 1H), 4.81 (d , J = 5.3 Hz, 1H), 4.18-4.08 (m, 1H), 4.08-3.91 (m, 3H), 3.83-3.72 (m, 1H), 2.43-2.16 (m, 2H); 1.58-1.44 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -4- (2- (1-fluoronaphthalen-2-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl sulfamate (I-119).

The title compound was prepared using 2- (1-fluoro-2-naphthyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1,488;

¹ H NMR (400 MHz, DMSO) δ 8.47-8.41 (m, 1H), 8.22-8.16 (m, 2H), 8.04 (d, J = 7.8 Hz, 1H ), 7.90 (d, J = 8.7 Hz, 1H), 7.81 (s, 1H), 7.72-7.63 (m, 2H), 6.94 (d, J = 4, 0 Hz, 1H), 6.32 (d, J = 5.4 Hz, 1H), 5.07 (s, 1H), 4.84 (s, 1H), 4.20-4.10 (m, 1H), 4.07-3.95 (m, 3H), 3.82-3.74 (m, 1H), 2.38-2.23 (m, 2H), 1.57-1.47 ( m, 1H).

(se) - ((1R, 2R, 3S, 4R) -4- (2- (4-fluoronaphthalen-2-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl sulfamate (I-118).

The title compound was prepared using 2- (4-fluoro-2-naphthyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1,488;

¹ H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 8.16 (d, J = 5.3 Hz, 1H), 8.15-8.05 (m, 3H), 7, 70-7.62 (m, 2H), 7.10 (s, 1H), 6.29 (d, J = 5.4 Hz, 1H), 5.75 (s, 1H), 5.05 (s , 1H), 4.14 (dd, J = 9.7, 5.9 Hz, 1H), 4.07-3.93 (m, 3H),

3.81-3.75 (m, 1H); 2.39-2.21 (m, 2H); 1.58-1.48 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -4- (2- (3-fluoronaphthalen-2-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl sulfamate (I-116).

The title compound was prepared using 2- (3-fluoro-2-naphthyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1,488;

¹ H NMR (400 MHz, DMSO) δ 8.80 (d, J = 7.7 Hz, 1H), 8.19 (d, J = 5.3 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.92-7.85 (m, 1H), 7.62-7.52 (m, 3H), 6.86 (d, J = 4.2 Hz, 1H), 6.33 (d, J = 5.4 Hz, 1H), 5.75 (s, 1H), 5.05 (d, J = 5 , 2 Hz, 1H), 4.21-4.10 (m, 1H), 4.10-3.94 (m, 3H), 3.83-3.74 (m, 1H), 2.40- 2.22 (m, 2H); 1.601.47 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -4- (2- (6-fluoronaphthalen-2-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl sulfamate (I-113).

The title compound was prepared using 2- (6-fluoro-2-naphthyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1,488;

¹ H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.15 (t, J = 4.7 Hz, 1H) 8.11-8.05 (m, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.78-7.73 (m, 1H), 7.51-7.44 (m, 2H), 7.03 (s, 1H), 6.27 (t, J = 5.7 Hz, 1H), 5.75 (s, 1H), 5.05 (d, J = 5, 3 Hz, 1H), 4.82 (s, 1H), 4.19-4.11 (m, 1H), 4.09-3.94 (m, 3H), 3.82-3.74 (m , 1H); 2.41-2.20 (m, 2H); 1.58-1.46 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (5-ethylbenzo [b] thiophen-3-yl) pyrazolo [1,5-a] pyrididin-7-ylamino) -2, 3-dihydroxycyclopentyl) methyl rel-sulfamate (I-94).

The title compound was prepared using 5-ethyl-1-benzothiophen-3-yl) boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 504;

¹ H NMR (400 MHz, DMSO) δ 8.15 (t, J = 5.1 Hz, 1H), 7.97 (d, J = 4.1 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.26 (dd, J = 8.3, 1.6 Hz, 1H), 6.95 ( d, J = 4.8 Hz, 1H), 6.29 (d, J = 5.5 Hz, 1H), 5.04 (s, 1H), 4.80 (s, 1H), 4.20- 4.09 (m, 1H), 4.08-3.92 (m, 3H), 3.82-3.72 (m, 1H), 2.73 (q, J = 7.5 Hz, 2H) 2.38-2.19 (m, 3H); 1.56-1.43 (m, 1H); 1.25 (t, J = 7.6 Hz, 3H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (5-ethylbenzo [b] thiophen-2-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2, 3-dihydroxycyclopentyl) methyl rel-sulfamate (I-95).

The title compound was prepared using (5-ethyl-1-benzothiophen-2-yl) boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 504;

¹ H NMR (400 MHz, DMSO) δ 8.50 (s, 1H), 8.26 (s, 1H), 8.19 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.71 (s, 1H), 7.33 (dd, J = 8.3, 1.5 Hz, 1H), 6.91 (s, 1H), 6, 31 (d, J = 5.4 Hz, 1H), 4.19-4.09 (m, 1H), 4.05-3.92 (m, 3H), 3.78 (t, J = 4, 8 Hz, 1H), 2.82 (q, J = 7.6 Hz, 2H), 2.41-2.19 (m, 3H), 1.55-1.43 (m, 1H), 1, 28 (t, J = 7.6 Hz, 3H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (benzofuran-3-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel sulfamate (I-49).

- 26 035020

The title compound was prepared using benzofuran-3-boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,460;

¹ H NMR (300 MHz, DMSO) δ 8.65 (s, 1H), 8.57-8.46 (m, 1H), 8.16 (d, J = 5.3 Hz, 1H), 7, 66 (dd, J = 9.2, 3.6

Hz, 2H), 7.41 (dd, J = 5.9, 3.2 Hz, 3H), 6.89 (s, 1H), 6.30 (d, J = 5.3 Hz, 1H), 4.22-4.11 (m, 1H); 4.09-3.95 (m,

3H), 3.85-3.73 (m, 1H), 2.39-2.22 (m, 2H), 1.60-1.48 (m, 1H).

(rac) - ((1P, 2K ^, 4K) -4- (2- (5-chlorobenzofuran-3-yl) pyrazolo [1,5-c] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel- sulfamate (I-92). The title compound was prepared using 5-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-benzofuran in step 1 instead of 1 naphthalenboronic acid. LCMS: (AA) M + 1,494;

¹ H NMR (300 MHz, DMSO) δ 8.75 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 5.3 Hz, 1H) , 7.72 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.8, 2.1 Hz, 1H), 6.31 (d, J = 5.4 Hz, 1H), 4.21-4.11 (m, 1H), 4.09-3.94 (m, 3H), 3.82-3.75 (m, 1H), 2.39-2.20 ( m, 3H), 1.61-1.48 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (6-chlorobenzo [b] thiophen-3-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2, 3-dihydroxycyclopentyl) methyl rel-sulfamate (I-91).

The title compound was prepared using (6-chloro-1-benzothiophen-2-yl) boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (FA) M + 1 510;

¹ H NMR (300 MHz, DMSO) δ 8.89 (d, J = 8.7 Hz, 1H), 8.39 (s, 1H), 8.25 (d, J = 1.9 Hz, 1H) 8.20-8.15 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.58-7.46 (m, 3H), 6.94 (s, 1H ), 6.32 (d, J = 5.5 Hz, 1H), 5.04 (s, 1H), 4.83 (s, 1H), 4.21-4.10 (m, 1H), 4 08-3.95 (m, 3H); 3.77 (s, 1H); 2.36-2.24 (m, 2H); 1.61-1.45 (m, 1H).

(rac) - ((III ^^^) - 2,3-dihydroxy-4- (2- (3- (2-propoxypropan-2-yl) phenyl) pyrazolo [1,5-c] pyrimidin-7-ylamino ) cyclopentyl) methyl rel-sulfamate (I-90).

The title compound was prepared using 4,4,5,5-tetramethyl-2- [3- (2-propoxypropan-2yl) phenyl] -1,3,2-dioxaborolan in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1,520.

(rac) - ((III ^^^) - 2,3-dihydroxy-4- (2- (3- (2-oxopyrrolidin-1-yl) phenyl) pyrazolo [1,5i] pyrimidin-7-ylamino) cyclopentyl ) methyl rel-sulfamate (I-87).

The title compound was prepared using 1- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) phenyl] pyrrolidin-2-one in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1 503;

¹ H NMR (300 MHz, DMSO) δ 8.21-8.08 (m, 2H), 7.91-7.82 (m, 1H), 7.80-7.70 (m, 1H), 7 , 53-7.41 (m, 2H), 6.89 (s, 1H), 6.31-6.23 (m, 1H), 4.18-4.08 (m, 1H), 4.06 -3.90 (m, 5H), 3.81-3.73 (m, 1H), 2.61-2.51 (m, 2H),

2.38-2.18 (m, 2H), 2.15-2.05 (m, 2H), 1.71 (s, 1H), 1.54-1.43 (m, 1H). (2-pyrrolidine protons in DMSO) (rac) - ((1R, 2R, 3S, 4R) -4- (2- (6-chlorobenzo [b] thiophen-2-yl) pyrazolo [1,5-a] pyrimidine -7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-88).

The title compound was prepared using (6-chloro-1-benzothien-3-yl) boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (FA) M + 1 510;

¹ H NMR (300 MHz, DMSO) δ 8.17 (d, J = 5.3 Hz, 1H), 8.04 (s, 1H), 7.89 (d, J = 8.6 Hz, 1H) , 7.66 (d, J = 7.4 Hz, 1H), 7.54-7.40 (m, 3H), 6.96 (d, J = 7.0 Hz, 1H), 6.31 ( d, J = 5.4 Hz, 1H), 5.04 (s, 1H), 4.80 (s, 1H), 4.19-4.09 (m, 1H), 4.08-3.91 (m, 3H), 3.82-3.72 (m, 1H), 2.35-2.20 (m, 2H), 1.60-1.43 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (3- (2-ethoxypropan-2-yl) phenyl) pyrazolo [1,5-a] pyrididin-7-ylamino) -

2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-84).

The title compound was prepared using 2- [3- (1-ethoxy-1-methylethyl) phenyl] -4,4,5,5tetramethyl-1,3,2-dioxaborolane in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1 506;

¹ H NMR (300 MHz, DMSO) δ 8.14 (d, J = 5.3 Hz, 1H), 8.02 (s, 1H), 7.99-7.94 (m, 1H), 7, 45 (d, J = 4.9 Hz, 2H), 6.90 (s, 1H), 6.26 (d, J = 5.4 Hz, 1H), 4.17-4.10 (m, 1H ), 4.07-3.93 (m, 3H), 3.80-3.73 (m, 1H), 3.23-3.15 (m, 3H), 2.39-2.19 (m , 2H), 1.53 (s, 6H), 1.10 (t, J = 7.0 Hz, 3H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (2-methoxypropan-2-yl) phenyl) pyrazolo [1,5-a] pyrididine- 7-ylamino) cyclopentyl) methyl rel-sulfamate (I-82). The title compound was prepared using 2- [3- (1-methoxy-1-methylethyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolan in step 1 instead of 1 naphthalenboronic acid. LCMS: (AA) M + 1 492;

¹ H NMR (300 MHz, DMSO) δ 8.13 (d, J = 5.3 Hz, 1H), 8.03 (s, 1H), 7.96 (d, J = 6.8 Hz, 1H) 7.49-7.39 (m, 2H), 6.90 (s, 1H), 6.29-6.22 (m, 1H), 4.18-4.10 (m, 1H), 4 07-3.93 (m, 3H), 3.79-3.73 (m, 1H), 3.01 (s, 3H),

2.38-2.22 (m, 2H); 1.52 (m, 7H).

(rac) - ((1R, 3S, 4R) -4- (2- (5-fluorobenzo [b] thiophen-3-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3- dihydroxycyclopentyl) methyl rel-sulfamate (I-81).

The title compound was prepared using (5-fluoro-1-benzothien-3-yl) boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (FA) M + 1 494;

¹ H NMR (300 MHz, DMSO) δ 8.71-8.64 (m, 1H), 8.21-8.09 (m, 2H), 7.85-7.79 (m, 1H), 7 52-7.45 (m, 1H),

7.39-7.31 (m, 1H), 6.95 (s, 1H), 6.34-6.29 (m, 1H), 5.03 (s, 1H), 4.82 (s, 1H) 4.19-4.11 (m, 1H); 4.08-3.94 (m, 3H); 3.81-3.75 (m, 1H); 2.39-2.21 (m, 2H), 1.60-1.50 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3-morpholinophenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl rel- sulfamate (I-78). The title compound was prepared using 3 (morpholino) phenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA)

- 27 035020

M + 1 505;

¹ H NMR (300 MHz, DMSO) δ 8.15-8.09 (m, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.35-7.29 (m , 1H), 6.99-6.93 (m, 1H), 6.91 (s, 1H), 6.28-6.22 (m, 1H), 5.08 (s, 1H), 4, 16-4.09 (m, 1H), 4.05-3.91 (m, 3H), 3.80-3.73 (m, 5H), 3.23-3.17 (m, 4H), 2.37-2.20 (m, 2H); 1.53-1.45 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,5-dihydroxy-4- (2- (3- (piperidin-1-yl) phenyl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl) methyl rel-sulfamate (I-77).

The title compound was prepared using 3- (piperidino) phenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 503.

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (3-benzoylphenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-73).

The title compound was prepared using 3-benzoylphenylboronic acid pinacol ester in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,524;

¹ H NMR (300 MHz, DMSO) δ 8.44 (s, 1H), 8.40-8.33 (m, 1H), 8.19-8.12 (m, 1H), 7.81-7 56 (m, 8H), 6.99 (s, 1H), 6.34-6.22 (m, 1H), 5.03 (s, 1H), 4.80 (s, 1H), 4, 17-4.07 (m, 1H), 4.06-3.90 (m, 3H), 3.80-3.68 (m, 1H), 2.35-2.20 (m, 2H), 1.54-1.43 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (5-chlorobenzo [b] thiophen-3-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2, 3-dihydroxycyclopentyl) methyl rel-sulfamate (I-71).

The title compound was prepared using (5-chloro-1-benzothien-3-yl) boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 510;

¹ H NMR (300 MHz, DMSO) δ 8.80-8.77 (m, 1H), 8.43 (s, 1H), 8.20-8.10 (m, 2H), 7.89-7 82 (m, 1H), 7.527.47 (m, 1H), 6.93 (s, 1H), 6.34-6.29 (m, 1H), 5.04 (s, 1H), 4, 83 (s, 1H), 4.18-4.10 (m, 1H), 4.06-3.95 (m, 3H),

3.81-3.75 (m, 1H); 2.38-2.22 (m, 2H); 1.59-1.48 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (3-benzylphenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-69).

The title compound was prepared using 3-benzylphenylboronic acid pinacol ester in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 510.

(rac) - [(1R, 2R, 3S, 4R) -4 - {[2- (3,3-dimethyl-1,3-dihydro-2-benzofuran-5-yl) pyrazolo [1,5-a] pyrimidin7-yl] amino} -2,3-dihydroxycyclopentyl] methyl rel-sulfamate (I-53).

The title compound was prepared using 1,1-dimethyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3-dihydro-2-benzofuran in step 1 instead of 1- naphthalene boronic acid. LCMS: (AA) M + 1 490;

¹ H NMR (300 MHz, DMSO) δ 8.16-8.11 (m, 1H), 8.03-7.98 (m, 1H), 7.94 (s, 1H), 7.52 (s , 1H), 7.37-7.33 (m, 1H), 6.92 (s, 1H), 6.27-6.23 (m, 1H), 5.75 (s, 1H), 5, 03 (s, 1H), 4.99 (s, 2H), 4.81 (s, 1H), 4.17-4.09 (m, 1H), 4.07-3.92 (m, 3H) 3.81-3.74 (m, 1H); 2.39-2.21 (m, 2H); 1.48 (s, 6H).

(rac) - ((III ^^^) - 4- (2- (dibenzo [b, b] furan-2-yl) pyrazolo [1,5-a] pyrimidin-7 -amino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-19). The title compound was prepared using 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) dibenzo [b, b] furan in step 1 instead of 1 naphthalenboronic acid. LCMS: (AA) M + 1,510;

¹ H NMR (300 MHz, DMSO) δ 8.85 (s, 1H), 8.30-8.25 (m, 1H), 8.22-8.18 (m, 1H), 8, 17-8 13 (m, 1H), 7.837.78 (m, 1H), 7.76-7.72 (m, 1H), 7.58-7.44 (m, 4H), 7.01 (s, 1H) ), 6.30-6.25 (m, 1H), 5.05-5.03 (m, 1H), 4.854.79 (m, 1H), 4.18-4.1 1 (m, 1H) 4.08-3.96 (m, 3H), 3.82-3.76 (m, 1H), 2.41-2.25 (m, 2H), 1.60-1.48 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (isoquinolin-4-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate (I-18). The title compound was prepared using 4-isoquinoline boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 471;

¹ H NMR (300 MHz, DMSO) δ 9.39 (s, 1H), 8.86 (s, 1H), 8.66-8.61 (m, 1H), 8.26-8.21 (m , 2H), 7.91-7.84 (m, 1H), 7.79-7.73 (m, 1H), 6.90 (s, 1H), 6.38-6.33 (m, 1H ), 4.14-4.08 (m, 1H), 4.04-3.95 (m, 3H), 3.78-3.71 (m, 1H), 2.39-2.21 (m , 2H), 1.57-1.47 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (pyrrolidin-1-yl) phenyl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl) methyl rel-sulfamate (I-46).

The title compound was prepared using 1- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) phenyl] pyrrolidine in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1,489.

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (quinolin-2-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate (I-42).

The title compound was prepared using quinoline-2-boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 471;

¹ H NMR (300 MHz, DMSO) δ 8.17 (d, J = 5.3 Hz, 1H), 8.04 (s, 1H), 7.89 (d, J = 8.6 Hz, 1H) , 7.66 (d, J = 7.4 Hz, 1H), 7.54-7.40 (m, 3H), 6.96 (d, J = 7.0 Hz, 1H), 6.31 ( d, J = 5.4 Hz, 1H), 5.04 (s, 1H), 4.80 (s, 1H), 4.19-4.09 (m, 1H), 4.08-3.91 (m, 3H), 3.82-3.72 (m, 1H), 2.35-2.20 (m, 2H), 1.60-1.43 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (quinolin-7-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate (I-43).

The title compound was prepared using quinolin-7-ylboronic acid in step 1 instead of 28 035020 one hundred 1-naphthalenboronic acid. LCMS: (AA) M + 1 471;

¹ H NMR (300 MHz, DMSO) δ 8.96-8.93 (m, 1H), 8.74 (s, 1H), 8.44-8.35 (m, 2H), 8.19-8 16 (m, 1H), 8.138.06 (m, 1H), 7.57-7.48 (m, 2H), 7.15 (s, 1H), 6.34-6.28 (m, 1H ), 5.06-5.03 (m, 1H), 4.81 (s, 1H), 4.18-4.11 (m,

1H), 4.08-3.96 (m, 3H), 3.79 (s, 1H), 3.17-3.14 (m, 1H), 2.40-2.22 (m, 2H) 1.60-1.48 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (7-chloroquinolin-4-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-39).

The title compound was prepared using 7-chloroquinoline-4boronic acid pinacol ester in step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M + 1 505;

¹ H NMR (300 MHz, DMSO) δ 9.07-9.02 (m, 1H), 8.84-8.78 (m, 1H), 8.28-8.23 (m, 1H), 8 20-8.15 (m, 1H), 7.92 (d, J = 4.5 Hz, 1H), 7.75-7.68 (m, 1H), 7.00 (s, 1H), 6.41-6.36 (m, 1H), 4.16-4.08 (m, 1H), 4.06-3.95 (m, 3H), 3.79-3.72 (m, 1H ), 2.39-2.20 (m, 2H), 1.57-1.46 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (quinolin-6-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate (I-34).

The title compound was prepared using quinoline-6-boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 471;

¹ H NMR (300 MHz, DMSO) δ 8.94-8.90 (m, 1H), 8.68 (s, 1H), 8.57-8.49 (m, 1H), 8.47-8 39 (m, 1H), 8.198.09 (m, 2H), 7.62-7.53 (m, 2H), 7.08 (s, 1H), 6.33-6.26 (m, 1H ), 5.04 (s, 1H), 4.17-4.10 (m, 1H), 4.08-3.94 (m, 3H), 3.81-3.76 (m, 1H), 2.40-2.21 (m, 2H); 1.59-1.47 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (5- (trifluoromethyl) quinolin-8-yl) pyrazolo [1,5-a] pyrimidin-7- ilamino) cyclopentyl) methyl rel-sulfamate (I-33).

The title compound was prepared using 5-trifluoromethylquinolin-8-boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 539;

¹ H NMR (300 MHz, DMSO) δ 9.22-9.16 (m, 1H), 8.79-8.70 (m, 1H), 8.58 (d, J = 8.7 Hz, 1H ), 8.26-8, 15 (m, 2H), 7.88-7.78 (m, 1H), 7.54 (s, 2H), 6.36-6.28 (m, 1H), 5.03 (s, 1H), 4.20-4.09 (m, 1H), 4.08-3.91 (m, 3H), 3.85-3.73 (m, 1H), 2, 39-2.20 (m, 2H); 1.60-1.45 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (isoquinolin-5-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate (I-27).

The title compound was prepared using isoquinolin-5-ylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 471;

¹ H NMR (300 MHz, DMSO) δ 9.40 (s, 1H), 8.61-8.49 (m, 2H), 8.25-8.15 (m, 3H), 7.82-7 78 (m, 1H), 7.45 (s, 1H), 6.87 (s, 1H), 6.38-6.30 (m, 1H), 5.04-5.00 (m, 1H ), 4.79 (m, 1H), 4.18-4.08 (m, 1H), 4.05-3.93 (m, 3H), 3.75 (s, 1H), 2.40- 2.21 (m, 2H); 1.59-1.45 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (quinolin-3-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate (I-25).

The title compound was prepared using 3-quinoline boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (FA) M + 1 471;

¹ H NMR (300 MHz, DMSO) δ 9.67 (s, 1H), 8.99 (s, 1H), 8.21-8.17 (m, 1H), 8.11-8.03 (m , 2H), 7.84-7.77 (m, 2H), 7.62 (s, 1H), 7.49 (s, 2H), 7.19-7.11 (m, 1H), 6, 39-6.27 (m, 1H), 5.06-5.02 (m, 1H), 4.90-4.75 (m, 1H), 4.21-4.11 (m, 1H), 4.08-3.92 (m, 3H), 3.85-3.75 (m, 1H), 2.36-2.27 (m, 1H), 1.63-1.46 (m, 1H) )

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (benzo [b] thiophen-3-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3- dihydroxycyclopentyl) methyl rel-sulfamate (I-22).

The title compound was prepared using thianaphthene-boronic acid in step 1 instead of 1-naphthalene boronic acid. (FA) M + 1 476;

¹ H NMR (300 MHz, DMSO) δ 8.89-8.81 (m, 1H), 8.34 (s, 1H), 8.24-8.13 (m, 1H), 8.10-8 02 (m, 1H), 7.66 (s, 1H), 7.55-7.44 (m, 3H), 6.93 (s, 1H), 6.35-6.24 (m, 1H ), 5.10-5.00 (m, 1H), 4.80 (s, 1H), 4.19-4.09 (m, 1H), 4.09-3.94 (m, 3H), 3.84-3.72 (m, 1H); 2.39-2.22 (m, 2H); 1.63-1.45 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (naphthalen-2-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate (I-16).

The title compound was prepared using 2-naphthalene boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 470;

¹ H NMR (300 MHz, DMSO) δ 8.63 (s, 1H), 8.30-8.26 (m, 1H), 8.17-8.14 (m, 1H), 8.06-7 93 (m, 3H), 7,607.53 (m, 2H), 7.52-7.45 (m, 1H), 7.05 (s, 1H), 6.32-6.26 (m, 1H ), 5.06-5.02 (m, 1H), 4.85-4.76 (m, 1H), 4.204.11 (m, 1H), 4.09-3.96 (m, 3H), 3.83-3.75 (m, 1H); 2.39-2.25 (m, 2H); 1.63-1.46 (m, 1H).

^^ - ^ R ^ R ^ S, 4R) -2,3-dihydroxy-4- (2- (2-methoxyphenyl) pyrazolo [1,5-c] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate ( I-72).

The title compound was prepared using 2-methoxyphenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,450;

¹ H NMR (400 MHz, DMSO) δ 8.26-8.21 (m, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.74-7.60 (m, 1H ), 7.45-7.35 (m, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.09-7.02 (m, 1H), 6.89 (s, 1H), 6.24 (d, J = 5.4 Hz, 1H), 4.17-4.08 (m, 1H), 4.07-

3.99 (m, 1H), 3.98-3.93 (m, 2H), 3.91 (s, 3H), 3.79-3.72 (m, 1H), 2.39-2, 27 (m, 1H), 2.27-2.16 (m, 1H), 1.551.42 (m, 1H).

- 29 035020 (rac) - ((1K, 2K, 38.4K) -2,3-dihydroxy-4- (2- (2-phenoxyphenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate (I-68).

The title compound was prepared using (2-phenoxyphenyl) borandiol in step 1 instead

1-naphthalene boronic acid. LCMS: (AA) M + 1 512;

¹ H NMR (400 MHz, DMSO) δ 8.39-8.32 (m, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.51-7.43 (m, 1H ), 7.39-7.30 (m, 3H), 7.13-7.03 (m, 2H), 6.96 (d, J = 7.8 Hz, 2H), 6.72 (s, 1H), 6.25 (d, J = 5.4 Hz, 1H), 4.19-4.08 (m, 1H), 4.08-

3.99 (m, 1H), 3.98-3.89 (m, 2H), 3.81-3.71 (m, 1H), 2.38-2.18 (m, 2H), 1, 55-1.41 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (3,3-dimethyl-2,3-dihydro-1H-inden-5-yl) pyrazolo [1,5-a] pyrimidine -7ylamino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-41).

The title compound was prepared using 2- (3,3-dimethyl-2,3-dihydro-III-inden-5-yl) (4,4,5,5-tetramethyl-1,3,2-dioxaborolan in step 1 instead 1-naphthalene boronic acid LCMS: (AA) M + 1 488;

¹ H NMR (400 MHz, DMSO) δ 8.12 (d, J = 5.3 Hz, 1H), 7.90-7.84 (m, 2H), 7.27 (d, J = 8.3 Hz, 1H), 6.87 (s, 1H), 6.24 (d, J = 5.4 Hz, 1H), 4.19-4.08 (m, 1H), 4.09-4.00 (m, 1H), 4.01-3.91 (m, 2H), 3.82-3.73 (m, 1H), 2.932.81 (m, 2H), 2.39-2.28 (m , 1H), 2.28-2.17 (m, 1H), 1.97-1.88 (m, 2H), 1.56-1.43 (m, 1H), 1.29 (s, 6H )

(rac) - ((W ^, 3 S, 4R) -4- (2- (5-chloro-2- (trifluoromethoxy) phenyl) pyrazolo [^^ pyrimidine ^ -amino) -2,3-dihydroxycyclopentyl) methyl rel Sulfamate (I-57).

The title compound was prepared using 5-chloro-2- (trifluoromethoxy) phenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,538;

¹ H NMR (400 MHz, DMSO) δ 8.39 (d, J = 2.7 Hz, 1H), 8.20 (d, J = 5.3 Hz, 1H), 7.96-7.83 ( m, 1H), 7.67-7.61 (m, 1H), 7.61-7.54 (m, 1H), 6.76 (s, 1H), 6.35 (d, J = 5, 4 Hz, 1H), 5.18-4.70 (m, 2H), 4.21-4.09 (m, 1H), 4.074.00 (m, 1H), 4.00-3.90 (m , 2H), 3.81-3.70 (m, 1H), 2.39-2.16 (m, 2H), 1.59-1.44 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) pyrazolo [1,5-a] pyrimidin-7ylamino) - 2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-26).

The title compound was prepared using 3,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) -2,3-dihydro-1-benzofuran in step 1 instead of 1- naphthalene boronic acid. LCMS: (AA) M + 1 490;

¹ H NMR (400 MHz, DMSO) δ 8.10 (d, J = 5.3 Hz, 1H), 7.94-7.88 (m, 1H), 7.88-7.81 (m, 1H ), 7.65-7.57 (m, 1H), 7.54-7.44 (m, 2H), 6.85 (d, J = 8.3 Hz, 1H), 6.80 (s, 1H), 6.22 (d, J = 5.4 Hz, 1H), 5.19-4.93 (m, 1H), 4.944.69 (m, 1H), 4.27 (s, 2H), 4.19-4.07 (m, 1H), 4.07-3.99 (m, 1H), 3.99-3.89 (m, 2H), 3.85-3.70 (m, 1H) ), 2,392.28 (m, 1H), 2.28-2.17 (m, 1H), 1.59-1.43 (m, 1H), 1.36 (s, 6H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (3,3-dimethyl-2,3-dihydrobenzofuran-7-yl) pyrazolo [1,5-a] pyrimidin-7ylamino) - 2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-23).

The title compound was prepared using 3,3-dimethyl-7- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) -2,3-dihydro-1-benzofuran in step 1 instead of 1- naphthalene boronic acid. LCMS: (AA) M + 1 490;

¹ H NMR (400 MHz, DMSO) δ 8.13 (d, J = 5.3 Hz, 1H), 8.09-8.04 (m, 1H), 7.69-7.60 (m, 1H ), 7.52-7.44 (m, 2H), 7.26-7.21 (m, 1H), 7.03-6.96 (m, 1H), 6.86 (s, 1H), 6.26 (d, J = 5.4 Hz, 1H), 5.08-4.96 (m, 1H), 4.85-4.66 (m, 1H), 4.39 (s, 2H) 4, 19-4.07 (m, 1H), 4.08-3.99 (m, 1H), 3.98-3.91 (m, 2H), 3.82-3.69 (m, 1H), 2.40-2.28 (m, 1H), 2.28-2.17 (m, 1H), 1.56-1.42 (m, 1H), 1.34 (s, 6H) .

(rac) - [(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (1H-indol-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclopentyl] methyl rel-sulfamate (I-24).

The title compound was prepared using 2-pinacolate boryl indole in step 1 instead of 1 naphthalene boronic acid. LCMS: (AA) M + 1,459;

¹ H NMR (400 MHz, DMSO) δ 1 1.56 (s, 1H), 8.16 (d, J = 5.3 Hz, 1H), 7.62-7.54 (m, 1H), 7 , 49-7.36 (m, 2H), 7.17-7.08 (m, 1H), 7.06-6.97 (m, 2H), 6.88 (s, 1H), 6.30 (d, J = 5.4 Hz, 1H), 5.17-4.99 (m, 1H), 4.99-4.74 (m, 1H), 4.20-4.09 (m, 1H ), 4.09-4.01 (m, 1H), 4.01-3.87 (m, 2H), 3.84-3.68 (m, 1H), 2.44-2.33 (m , 1H); 2.32-2.19 (m, 1H); 1.52-1.35 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (5-chloro-2-methoxyphenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel sulfamate (I-20).

The title compound was prepared using (5-chloro-2-methoxyphenyl) boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 484;

¹ H NMR (400 MHz, DMSO) δ 8.35-8.25 (m, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.83-7.72 (m, 1H ), 7.52-7.46 (m, 2H), 7.46-7.39 (m, 1H), 7.19 (d, J = 9.0 Hz, 1H), 6.94 (s, 1H), 6.27 (d, J = 5.4 Hz, 1H), 5.09-4.96 (m, 1H), 4.884.71 (m, 1H), 4.19-4.08 (m , 1H), 4.07-4.00 (m, 1H), 4.01-3.95 (m, 2H), 3.94 (s, 3H), 3.81-3.66 (m, 1H ), 2,372.18 (m, 2H), 1.56-1.40 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (5-chloro-2-methylphenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-21).

The title compound was prepared using 5-chloro-2-methylphenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1,468;

¹ H NMR (400 MHz, DMSO) δ 8.17 (d, J = 5.3 Hz, 1H), 7.84-7.69 (m, 2H), 7.52-7.42 (m, 2H ), 7.41-7.33 (m, 2H), 6.72 (s, 1H), 6.29 (d, J = 5.4 Hz, 1H), 5.08-4.92 (m, 1H), 4.86-4.66 (m, 1H), 4.17-4.06 (m, 1H), 4.06-3.98

- 30 035020 (m, 1H), 3.98-3.89 (m, 2H), 3.79-3.63 (m, 1H), 3.33 (s, 3H), 2.36-2, 17 (m, 2H); 1.55-1.39 (m, 1H).

(rac) - ((1K, 2K, 38.4K) -2,3-dihydroxy-4- (2- (3- (trimethylsilyl) phenyl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl) methyl rel sulfamate (I-35).

The title compound was prepared using 3-trimethylsilylphenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 492.3;

¹ H NMR (400 MHz, DMSO) δ 8.18-8.12 (m, 2H), 8.11-8.06 (m, 1H), 7.68 (d, J = 7.8 Hz, 1H ), 7.55 (d, J = 7.3 Hz, 1H), 7.51-7.42 (m, 3H), 6.94 (s, 1H), 6.26 (d, J = 5, 4 Hz, 1H), 5.03 (d, J = 5.6 Hz, 1H), 4.81 (d, J = 5.2 Hz, 1H), 4.13 (dd, J = 9.7, 6.0 Hz, 1H), 4.06-3.89 (m, 3H), 3.77 (dd, J = 10.0, 5.0 Hz, 1H), 2.39-2.17 (m , 2H), 1.56-1.42 (m, 1H), 0.31 (s, 9H).

(rac) - {(1R, 2R, 3S, 4R) -4 - [(2- {3 - [(cyclopropylmethyl) sulfanyl] phenyl} pyrazolo [1,5-a] pyrimidin-7yl) amino] -2.3 -dihydroxycyclopentyl} methyl rel-sulfamate (I-76).

The title compound was prepared using 3- (cyclopropylmethyl) thiophenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 506;

¹ H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.5 Hz, 1H), 8.07 (s, 1H), 7.90-7.73 (m, 1H), 7, 45-7.30 (m, 2H), 6.77 (s, 1H), 6.32 (d, J = 5.6 Hz, 1H), 4.28-4.06 (m, 3H), 4 05-3.90 (m, 2H), 2.99-2.83 (m, 2H), 2.55-2.29 (m, 2H), 1.63-1.44 (m, 1H) 1.13-0.96 (m, 1H); 0.60-0.47 (m, 2H); 0.37-0.18 (m, 2H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (1H-indol-4-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclopentyl] methyl rel-sulfamate (I-75).

The title compound was prepared using 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) III-indole in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 459;

¹ H NMR (400 MHz, MeOD) δ 8.15 (d, J = 5.5 Hz, 1H), 7.68-7.59 (m, 1H), 7.51-7.43 (m, 1H ), 7.36 (d, J = 3.2 Hz, 1H), 7.25-7.17 (m, 1H), 7.14-7.09 (m, 1H), 6.85 (s, 1H), 6.33 (d, J = 5.6 Hz, 1H), 4.31-4.18 (m, 2H), 4.184.09 (m, 1H), 4.09-4.02 (m , 1H), 4.02-3.95 (m, 1H), 2.61-2.49 (m, 1H), 2.49-2.36 (m, 1H), 1.69-1.54 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (4-fluoro-2-methoxyphenyl) pyrazolo [1,5ш] pyrimidin-7 -amino) -2,3-dihydroxycyclopentyl) methyl rel Sulfamate (I-70).

The title compound was prepared using 4-fluoro-2-methoxyphenylboronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 468;

¹ H NMR (300 MHz, MeOD) δ 8.27-8.16 (m, 1H), 8.12 (d, J = 5.5 Hz, 1H), 6.97-6.86 (m, 2H ), 6.84-6.72 (m, 1H), 6.30 (d, J = 5.6 Hz, 1H), 4.31-4.17 (m, 2H), 4.15-3, 91 (m, 6H), 2.61-2.33 (m, 2H), 1.69-1.50 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (2- (trifluoromethyl) pyridin-4-yl) pyrazolo [1,5-a] pyrimidin-7- amylamino) cyclopentyl) methyl rel-sulfamate (I-59).

The title compound was prepared using 2- (trifluoromethyl) pyridin-4-boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 489;

¹ H NMR (300 MHz, MeOD) δ 8.78 (d, J = 5.1 Hz, 1H), 8.62-8.46 (m, 1H), 8.35-8.22 (m, 1H ), 8.19 (d, J = 5.5 Hz, 1H), 7.05 (s, 1H), 6.40 (d, J = 5.6 Hz, 1H), 4.35-3.88 (m, 5H), 2.60-2.35 (m, 2H), 1.73-1.51 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (2-methoxy-5- (trifluoromethylthio) phenyl) pyrazolo [1,5a] pyrimidin-7-ylamino ) cyclopentyl) methyl sulfamate (I-120).

The title compound was prepared using {2-methoxy-5 [(trifluoromethyl) sulfanyl] phenyl} boronic acid in step 1 instead of 1-naphthalene boronic acid. LCMS: (AA) M + 1 550;

¹ H NMR (400 MHz, MeOD) δ 8.58 (d, J = 2.4 Hz, 1H), 8, 17 (d, J = 5.5 Hz, 1H), 7.82-7.61 ( m, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.02 (s, 1H), 6.36 (d, J = 5.5 Hz, 1H), 4.31- 4.11 (m, 3H), 4.10-4.03 (m, 4H), 4.02-3.96 (m, 1H), 2.64-2.34 (m, 2H), 1, 71-1.51 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -4- (2- (2,4-dichloronaphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl sulfamate (I-117).

The title compound was prepared using 2- (2,4-dichloro-1-naphthyl) -4,4,5,5-tetramethyl1,3,2-dioxaborolane in step 1 instead of 1-naphthalenboronic acid. LCMS: (AA) M + 1,538;

¹ H NMR (400 MHz, MeOD) δ 8.31 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 5.5 Hz, 1H), 7.81 (s, 1H) 7.70-7.58 (m, 2H), 7.56-7.48 (m, 1H), 6.56 (s, 1H), 6.41 (d, J-5.6 Hz, 1H ), 4.23-4.07 (m, 3H), 4.02-3.95 (m, 1H), 3.95-3.87 (m, 1H), 2.56-2.31 (m , 2H); 1.55-1.42 (m, 1H).

Example 8. Compounds obtained using method B (rac) - ((1R, 2R, 3S, 4R) -4- (2- (biphenyl-3-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino ) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-3).

The title compound was prepared using methyl biphenyl-3-carboxylate in step 1 instead of ethyl α-naphthoate. LCMS: (AA) M + 1,496;

¹ H NMR (300 MHz, MeOD) δ 8.39-8.30 (m, 1H), 8.13 (d, J = 5.5 Hz, 1H), 8.04-7.95 (m, 2H ), 7.72-7.28 (m, 9H), 6.85 (s, 1H), 6.31 (d, J-5.6 Hz, 1H), 4.27-4.04 (m, 3H), 4.01-3.87 (m, 2H), 2.56-2.30 (m, 2H), 1.59-1.43 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2-phenylpyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate (I-1 )

The title compound was prepared starting from 5-amino-3-phenylpyrazole and following from step 2b to step 7. LCMS: (AA) M + 1 420;

- 31 035020 ¹ H NMR (300 MHz, MeOD) δ 8.12 (d, J = 5.5 Hz, 1H), 8.07-7.99 (m, 2H), 7.49-7.36 ( m, 3H), 6.76 (s, 1H),

6.31 (d, J = 5.6 Hz, 1H), 4.28-3.91 (m, 5H), 2.59-2.33 (m, 2H), 1.67-1.51 ( m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4 - ((2- (3- (tert-butyl) phenyl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) -2, 3-dihydroxycyclopentyl) methyl rel-sulfamate (I-15).

The title compound was prepared using 3-tert-butylbenzoic acid ethyl ester in step 1 instead of ethyl α-naphthoate. LCMS: (FA) M + 1 476;

¹ H NMR (400 MHz, DMSO) δ 8.13 (d, J = 5.3 Hz, 1H), 8.04 (s, 1H), 7.90 (d, J = 7.3 Hz, 1H) , 7.65 (d, J = 8.0 Hz, 1H), 7.46-7.36 (m, 3H), 6.92 (s, 1H), 6.26 (d, J = 5.3 Hz, 1H), 5.04 (s, 1H), 4.82 (s, 1H), 4.18-4.08 (m, 1H), 4.08-3.88 (m, 3H), 3 81-3.73 (m, 1H); 2.39-2.18 (m, 3H); 1.57-1.43 (m, 1H); 1.36 (s, 9H).

(rac) - ((1R, 2R, 3S, 4R) -4 - ((2- (3-chlorophenyl) pyrazolo [1,5-a] pyrimidin-7-yl) amino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-5).

The title compound was prepared using ethyl 3-chlorobenzoate in step 1 instead of ethyl α-naphthoate. LCMS: (FA) M + 1,454.

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((2- (3- (trifluoromethyl) phenyl) pyrazolo [1,5-a] pyrimidin-7yl) amino) cyclopentyl ) methyl rel-sulfamate (I-7).

The title compound was prepared using 3- (trifluoromethyl) benzoic acid in step 1 instead of ethyl α-naphthoate. LCMS: M + 1,488;

¹ H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 8.32-8.24 (m, 1H), 8.19-8.11 (m, 1H), 7.73-7 , 61 (m, 2H), 6.87 (s, 1H), 6.35 (d, J = 5.5 Hz, 1H), 4.28-4.18 (m, 2H), 4.18- 4.09 (m, 1H), 4.08-4.03 (m, 1H), 4.01-3.96 (m, 1H), 2.58-2.35 (m, 2H), 1, 67-1.54 (m, 1H).

(rac) - [(1R, 2R, 3S, 4R) -4 - {[2- (2,4-dichlorophenyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2,3-dihydroxycyclopentyl ] methyl rel-sulfamate (I-13).

The title compound was prepared starting from 5- (2,4-dichloro-phenyl) -2H-pyrazol-3-ylamine hydrochloride and from step 2b to step 7. LCMS: (AA) M + 1 488;

¹ H NMR (400 MHz, MeOD) δ 8.17 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H) 7.46-7.40 (m, 1H), 6.90 (s, 1H), 6.37 (d, J = 5.4 Hz, 1H), 4.27-4.17 (m, 2H ), 4.16-4.07 (m, 1H), 4.05-4.00 (m, 1H), 3.99-3.94 (m, 1H), 2.57-2.47 (m , 1H); 2.46-2.35 (m, 1H); 1.65-1.51 (m, 1H).

Example 9. Compounds obtained by the method C (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (2-isopropoxynaphthalen-1-yl) pyrazolo [1,5 -a] pyrimidin7-ylamino) cyclopentyl) methyl sulfamate (I-109).

The title compound was prepared using 1-bromo-2-isopropoxynaphthalene-1-bromo-2naphthyl isopropyl in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1,528;

¹ H NMR (400 MHz, MeOD) δ 8.20 (d, J = 5.5 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.87-7.80 ( m, 1H), 7.71-7.63 (m, 1H), 7.45 (d, J = 9.1 Hz, 1H), 7.38-7.31 (m, 2H), 6.54 (s, 1H), 6.37 (d, J = 5.6 Hz, 1H), 4.67-4.59 (m, 1H), 4.23-4.06 (m, 3H), 4, 02-3.95 (m, 1H), 3.94-3.89 (m, 1H), 2.58-2.46 (m, 1H), 2.45-2.34 (m, 1H), 1.56-1.44 (m, 1H); 1.20 (d, J = 6.1 Hz, 6H).

(rac) - ((^^^^) - 4- (2- (dibenzo [bD] furan-3-yl) pyrazolo [1,5-a] pyrimidin-7 -amino) -2,3-dihydroxycyclopentyl) methyl rel- sulfamate (I-93).

The title compound was prepared using 3-bromodibenzo [L] furan in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (Aa) M + 1,510;

¹ H NMR (400 MHz, DMSO) δ 8.29 (d, J = 7.9 Hz, 1H), 8.25 (d, J = 5.3 Hz, 1H), 7.82-7.78 ( m, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.71-7.67 (m, 1H), 7.66-7.60 (m, 1H), 7.56 -7.50 (m, 1H), 7.34-7.25 (m, 1H), 6.85 (s, 1H), 6.37 (d, J = 5.5 Hz, 1H), 4, 15-4.05 (m, 1H), 4.02-3.90 (m, 3H), 3.78-3.71 (m, 1H), 2.41-2.31 (m, 1H), 2.29-2.19 (m, 1H); 1.54-1.42 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4 - {[2- (5-tert-butyl-2-methoxyphenyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -

2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-63).

The title compound was prepared using 4-tert-butyl-2-iodo-1-methoxybenzene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1 506;

¹ H NMR (400 MHz, DMSO + D20) δ 8.12 (d, J = 5.3 Hz, 1H), 8.06-8.01 (m, 1H), 7.43-7.37 (m , 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.82 (s, 1H), 6.24 (d, J = 5.4 Hz, 1H), 4.17-4 07 (m, 1H), 4.07-3.98 (m, 1H), 3.99-3.89 (m, 2H), 3.85 (s, 3H), 3.79-3.70 (m, 1H), 2.37-2.28 (m, 1H), 2.28-2.18 (m, 1H), 1.52-1.42 (m, 1H), 1.31 (s , 9H).

(rac) - ((^^^^) - 2,3-dihydroxy-4- (2- (9-oxo-9H-fluoren-2-yl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl) methyl rel-sulfamate (I-85).

The title compound was prepared using 2-bromofluoren-9-one in step 2 instead of 1-chloro-

4-iodine-naphthalene. LCMS: (AA) M + 1,522;

¹ H NMR (400 MHz, DMSO) δ 8.42-8.36 (m, 1H), 8.35-8.29 (m, 1H), 8.15 (d, J = 5.3 Hz, 1H ), 7.93 (d, J = 7.8 Hz, 1H), 7.90-7.84 (m, 1H), 7.84-7.77 (m, 1H), 7.69-7, 62 (m, 2H), 7.58-7.44 (m, 2H), 7.45-7.36 (m, 1H), 7.05 (s, 1 H), 6.29 (d, J = 5.4 Hz, 1H), 5.16-4.97 (m, 1H), 4.94-4.70 (m, 1H), 4.20-4.08 (m, 1H), 4, 08-3.92 (m, 3H), 3.85-3.71 (m, 1H), 2.40-2.19 (m, 2H), 1.59-1.45 (m, 1H).

(rac) - (1R, 2R, 3S, 4R) -4- (2- (3-cyclopentenylphenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate ( I-47). The title compound was prepared using 1 bromo-3-cyclopent-1-en-1-ylbenzene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1,486;

- 32 035020 ¹ H NMR (400 MHz, DMSO) δ 8.21-8.09 (m, 2H), 7.99-7.91 (m, 1H), 7.74-7.64 (m, 1H ), 7.51-7.41 (m, 3H),

6.96 (s, 1H), 6.47-6.36 (m, 1H), 6.30-6.22 (m, 1H), 5.14-4.97 (m, 1H), 4, 91-4.73 (m, 1H), 4.19-4.09 (m, 1H),

4.08-3.89 (m, 3H), 3.83-3.72 (m, 1H), 2.76 (d, m, 2H), 2.39-2.18 (m, 2H), 2.10-1.94 (m, 2H); 1.61-1.41 (m, 1H).

(rac) - ((1K, 2K ^, 4K) -2,3-dihydroxy-4- (2- (3- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl) pyrazolo [1 , 5-c] pyrimidin-7-ylamino) cyclopentyl) methyl rel-sulfamate (I-58).

The title compound was prepared using 1-iodo-3- (2,2,2-trifluoro-1,1-dimethylethyl) benzene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1,530;

¹ H NMR (400 MHz, DMSO) δ 8.18-8.12 (m, 2H), 8.12-8.06 (m, 1H), 7.71-7.62 (m, 1H), 7 , 61-7.55 (m, 1H), 7.55-7.48 (m, 2H), 7.00 (s, 1H), 6.28 (d, J = 5.4 Hz, 1H), 5.13-4.94 (m, 1H), 4.93-4.70 (m, 1H), 4.20-4.08 (m, 1H), 4.08-4.00 (m, 1H) ), 4.00-3.90 (m, 2H), 3.82-3.66 (m, 1H), 2.40-2.29 (m, 1H), 2.28-2.16 (m , 1H); 1.64 (s, 6H); 1.54-1.41 (m, 1H).

(s.e.) - ((1R, 2R, 3S, 4R) -4- (2- (2- (difluoromethoxy) naphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -

2,3-dihydroxycyclopentyl) methyl sulfamate (I-110).

The title compound was prepared using 1-bromo-2- (difluoromethoxy) naphthalene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1,536;

¹ H NMR (400 MHz, MeOD) δ 8.23 (d, J = 5.5 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 8.01-7.89 ( m, 1H), 7.83-7.71 (m, 1H), 7.59-7.40 (m, 3H), 6.83 (t, J = 74.5 Hz, 1H), 6.59 (s, 1H), 6.42 (d, J = 5.7 Hz, 1H), 4.24-4.08 (m, 3H), 4.03-3.96 (m, 1H), 3, 95-3.88 (m, 1H), 2.57-2.45 (m, 1H), 2.45-2.32 (m, 1H), 1.59-1.41 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (4-methylnaphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl) methyl sulfamate (I-115).

The title compound was prepared using 1-bromo-4-methyl-naphthalene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1 484;

¹ H NMR (300 MHz, MeOD) δ 8.50-8.40 (m, 1H), 8.20 (d, J = 5.5 Hz, 1H), 8.15-8.03 (m, 1H ), 7.67 (d, J = 7.2 Hz, 1H), 7.62-7.48 (m, 2H), 7.46-7.38 (m, 1H), 6.66 (s, 1H), 6.38 (d, J = 5.6 Hz, 1H), 4.29-4.08 (m, 3H), 4.05-

3.99 (m, 1H), 3.98-3.90 (m, 1H), 2.75 (s, 3H), 2.61-2.32 (m, 2H), 1.63-1, 46 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (2-methylnaphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl ) methyl sulfamate (I-114).

The title compound was prepared using 1-bromo-2-methylnaphthalene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1 484;

¹ H NMR (400 MHz, MeOD) δ 8.19 (d, J = 5.5 Hz, 1H), 7.93-7.79 (m, 2H), 7.52-7.36 (m, 3H ), 7.36-7.26 (m, 1H), 6.47 (s, 1H), 6.36 (d, J = 5.6 Hz, 1H), 4.22-4.03 (m, 3H), 4.01-3.93 (m, 1H), 3.93-3.83 (m, 1H), 2.54-2.28 (m, 5H), 1.54-1.33 ( m, 1H).

(s.e.) - ((1R, 2R, 3S, 4R) -4- (2- (4- (difluoromethoxy) naphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -

2,3-dihydroxycyclopentyl) methyl sulfamate (I-112).

The title compound was prepared using 1- (difluoromethoxy) -4-iodo-naphthalene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1,536;

¹ H NMR (400 MHz, MeOD) δ 8.56-8.47 (m, 1H), 8.30-8.23 (m, 1H), 8.20 (d, J = 5.5 Hz, 1H ), 7.78 (d, J = 8.0 Hz, 1H), 7.69-7.56 (m, 2H), 7.33 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 73.8 Hz, 1H), 6.69 (s, 1H), 6.38 (d, J = 5.5 Hz, 1H), 4.26-4.08 (m, 3H) 4.07-3.99 (m, 1H); 3.99-3.90 (m, 1H); 2.58-2.35 (m, 2H); 1.62-1.47 (m, 1H).

(s.e.) - ((1R, 2R, 3S, 4R) -4- (2- (6- (difluoromethyl) naphthalen-1-yl) pyrazolo [1,5-c] pyrimidin-7 -ylamino) -

2,3-dihydroxycyclopentyl) methyl sulfamate (I-111).

The title compound was prepared using 1-bromo-6- (difluoromethyl) naphthalene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1,520;

¹ H NMR (400 MHz, MeOD) δ 8.64 (d, J = 8.9 Hz, 1H), 8.21 (d, J = 5.5 Hz, 1H), 8.17-8.12 ( m, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.95-7.87 (m, 1H), 7.73-7.63 (m, 2H), 6.94 (t, J = 56.1 Hz, 1H), 6.73 (s, 1H), 6.40 (d, J = 5.7 Hz, 1H), 4.29-4.07 (m, 3H) , 4.07-4.00 (m, 1H), 3.99-3.90 (m, 1H), 2.60-2.46 (m, 1H), 2.46-2.33 (m, 1H), 1.63-1.48 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (2-methoxynaphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl) methyl sulfamate (I-104).

The title compound was prepared using 1-bromo-2-methoxynaphthalene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1,500;

¹ H NMR (400 MHz, MeOD) δ 8.20 (d, J = 5.5 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.91-7.77 ( m, 1H), 7.72-7.56 (m, 1H), 7.50 (d, J = 9.1 Hz, 1H), 7.40-7.23 (m, 2H), 6.51 (s, 1H), 6.40-6.28 (m, 1H), 4.28-4.05 (m, 3H), 4.013.95 (m, 1H), 3.95-3.89 (m , 1H), 3.87 (s, 3H), 2.59-2.45 (m, 1H), 2.45-2.35 (m, 1H), 1.57-1.41 (m, 1H) )

(s.e.) - ((1R, 2R, 3S, 4R) -4- (2- (4- (dimethylamino) naphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -

2,3-dihydroxycyclopentyl) methyl sulfamate (I-107).

The title compound was prepared using 1-bromo-4- (dimethylamino) naphthalene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1 513;

¹ H NMR (400 MHz, MeOD) δ 8.50-8.39 (m, 1H), 8.36-8.26 (m, 1H), 8.19 (d, J = 5.5 Hz, 1H ), 7.71 (d, J = 7.8 Hz, 1H), 7.58-7.41 (m, 2H), 7.21 (d, J = 7.8 Hz, 1H), 6.64 (s, 1H), 6.37 (d, J = 5.6 Hz, 1H), 4.28-4.08 (m, 3H), 4.07-3.99 (m, 1H), 3, 99-3.91 (m, 1H), 2.93 (s, 6H), 2.58-2.47 (m, 1H), 2.47-2.32 (m, 1H), 1.62- 1.47 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (4-methoxynaphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7-33 035020 ilamino ) cyclopentyl) methyl sulfamate (I-106).

The title compound was prepared using 1-iodo-4-methoxy-naphthalene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 1,500;

¹ H NMR (400 MHz, MeOD) δ 8.49-8.39 (m, 1H), 8.35-8.26 (m, 1H), 8, 17 (d, J = 5.5 Hz, 1H ), 7.73 (d, J = 8.0 Hz, 1H), 7.58-7.43 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 6.35 (d, J = 5.5 Hz, 1H), 4.26-4.08 (m, 3H), 4.06 (s, 3H), 4.04-3, 98 (m, 1H), 3.98-3.92 (m, 1H), 2.58-2.45 (m, 1H), 2.45-2.32 (m, 1H), 1.60- 1.45 (m, 1H).

(se) - ((1R, 2R, 3S, 4R) -4- (2- (5-fluoronaphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl sulfamate (I-105).

The title compound was prepared using 1-bromo-5-fluoro-naphthalene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (Aa) M + 1,488;

¹ H NMR (400 MHz, MeOD) δ 8.30 (d, J = 8.6 Hz, 1H), 8.24-8.16 (m, 2H), 7.93-7.84 (m, 1H ), 7.72-7.61 (m, 1H), 7.54-7.43 (m, 1H), 7.30-7.20 (m, 1H), 6.71 (s, 1H), 6.40 (d, J = 5.5 Hz, 1H), 4.27-4.08 (m, 3H), 4.07-3.99 (m, 1H), 3.99-3.91 ( m, 1H), 2.60-2.47 (m, 1H), 2.46-2.36 (m, 1H), 1.63-1.49 (m, 1H).

(rac) methyl n-5- [7 - ({(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoyloxy) methyl] cyclopentyl} amino) pyrazolo [1,5-a ] pyrimidin-2-yl] -2-naphthoate (I-96).

The title compound was prepared using methyl 5-bromo-2-naphthoate in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (Aa) M + 1,528;

¹ H NMR (300 MHz, DMSO + D20) δ 8.72 (s, 1H), 8.62 (d, J = 9.0 Hz, 1H), 8.30-8.16 (m, 2H), 8.08-7.93 (m, 2H), 7.77-7.64 (m, 1H), 6.80 (s, 1H), 6.34 (d, J = 5.5 Hz, 1H) 4.16-3.87 (m, 7H), 3.77-3.69 (m, 1H), 2.42-2.14 (m, 2H), 1.56-1.41 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (5-fluoronaphthalen-1-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-97). The title compound was prepared using 1 bromo-5-fluoronaphthalene in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 488;

¹ H NMR (300 MHz, DMSO) δ 8.32 (d, J = 8.6 Hz, 1H), 8.27-8.11 (m, 2H), 7.93 (d, J = 7.0 Hz, 1H), 7.78-7.66 (m, 1H), 7.63-7.51 (m, 1H), 7.48-7.34 (m, 1H), 6.78 (s, 1H), 6.34 (d, J = 5.3 Hz, 1H), 4.19-4.07 (m, 1H), 4.073.92 (m, 3H), 3.81-3.67 (m , 1H); 2.44-2.13 (m, 2H); 1.61-1.14 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (4- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl) methyl rel sulfamate (I-80).

The title compound was prepared using 4-bromophenyl trifluoromethyl sulfide in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 520;

¹ H NMR (400 MHz, MeOD) δ 8.25-8.10 (m, 3H), 7.77 (d, J = 8.3 Hz, 2H), 6.86 (s, 1H), 6, 35 (d, J = 5.6 Hz, 1H), 4.30-4.18 (m, 2H), 4.17-4.08 (m, 1H), 4.07-4.02 (m, 1H), 4.02-3.95 (m, 1H), 2.59-2.35 (m, 2H), 1.67-1.53 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (2- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7ylamino) cyclopentyl) methyl rel sulfamate (I-79).

The title compound was prepared using 2-bromophenyl trifluoromethyl sulfide in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 520;

¹ H NMR (400 MHz, MeOD) δ 8.21 (d, J = 5.8 Hz, 1H), 7.96-7.90 (m, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.69-7.62 (m, 1H), 7.60-7.51 (m, 1H), 6.76 (s, 1H), 6.45 (d, J = 5, 9 Hz, 1H), 4.27-4.12 (m, 3H), 4.07-3.99 (m, 1H), 3.983.90 (m, 1H), 2.57-2.33 (m , 2H); 1.66-1.52 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (6- (trifluoromethyl) pyridin-2-yl) pyrazolo [1,5-a] pyrimidin-7- ilamino) cyclopentyl) methyl rel-sulfamate (I-64).

The title compound was prepared using 2-bromo-6- (trifluoromethyl) pyridine in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 489;

¹ H NMR (400 MHz, MeOD) δ 8.49 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 5.5 Hz, 1H), 8.15-8.07 ( m, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.07 (s, 1H), 6.38 (d, J = 5.6 Hz, 1H), 4.32- 4.18 (m, 2H), 4.18-4.09 (m, 1H), 4.08-3.94 (m, 2H), 2.62-2.50 (m, 1H), 2, 48-2.36 (m, 1H); 1.69-1.55 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (6-tert-butylpyridin-2-yl) pyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-52).

The title compound was prepared using 2-bromo-6-tert-butylpyridine in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M + 477;

¹ H NMR (400 MHz, MeOD) δ 8.15 (d, J = 5.5 Hz, 1H), 8.10-7.95 (m, 1H), 7.85-7.71 (m, 1H ), 7.48-7.35 (m, 1H), 7.03 (s, 1H), 6.34 (d, J = 5.5 Hz, 1H), 4.30-4.19 (m, 2H), 4.17-4.08 (m, 1H), 4.07-3.96 (m, 2H), 2.61-2.33 (m, 2H), 1.71-1.52 ( m, 1H); 1.43 (s, 9H).

(ratG ^ W ^^^^^ - ^ Dbenzofuran ^ -yl ^ and irazoloCD ^ pyrimidine ^ -amino ^ D-dihydroxycyclopentyl) methyl rel-sulfamate (I-86).

The title compound was prepared using 2-iodo-1-benzofuran in step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (FA) M + 1,460.2;

¹ H NMR (400 MHz, DMSO) δ 8.19 (d, J = 5.3 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.697.65 (m, 1H), 7.53-7.44 (m, 2H), 7.40-7.34 (m, 1H), 7.34-7.26 (m, 1H), 6.93 (s, 1H), 6.32 (d, J = 5.4 Hz, 1H), 5.04 (s, 1H), 4.80 (s, 1H), 4 , 17-4.07 (m, 1H), 4.07-3.89 (m, 3H), 3.78 (s, 1H), 2.40-2.13 (m, 2H), 1.58 -1.44 (m, 1H).

- 34 035020

Method C with modification [example 10]

Example 10. Synthesis of (rac) - [(1K, 2K, 38.4K) -4 - {[2- (3-cyclopentylphenyl) pyrazolo [1,5-a] pyrimidin-7yl] amino} -2,3-dihydroxycyclopentyl ] methyl rel-sulfamate (I-48).

Stage 1: (rac) -rel - [(3aR, 4R, 6R, 6aS) -6 - {[2- (3-cyclopentylphenyl) pyrazolo [1,5-a] pyrimidin-7yl] amino} -2,2- dimethyltetrahydro-3aH-cyclopenta [d [1,3] dioxol-4-yl] methanol (rac) -rel - [(3aR, 4R, 6R, 6aS) -6 - ({2- [3- (cyclopent-1- en-1-yl) phenyl] pyrazolo [1,5-a] pyrimidin-7yl} amino) -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl] methanol (0.039 g , 0.087 mmol) was stirred in ethanol (2.3 ml, 39 mmol). Palladium hydroxide (4.0 mg, 0.020 mmol) was added and the reaction mixture was stirred under a bottle of hydrogen overnight.

The reaction mixture was filtered through celite, washed with ethanol and concentrated in vacuo to give (rac) -rel - [(3aR, 4R, 6R, 6aS) -6 - {[2- (3-cyclopentylphenyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl] methanol (39 mg, 100% yield). Used in the next step without further purification.

Step 2: (race) - [(1R, 2R, 3S, 4R) -4 - {[2- (3-cyclopentylphenyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -

2,3-dihydroxycyclopentyl] methyl rel-sulfamate (I-48)

The title compound was synthesized from (rac) -rel - [(3aR, 4R, 6R, 6aS) -6 - {[2- (3-cyclopentylphenyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2 , 2-dimethyltetrahydro-3aH-cyclopenta ^] [1,3] dioxol-4-yl] methanol, following step 2 of method A (product yield 44%). LCMS: (AA) M + 1,488;

¹ H NMR (400 MHz, DMSO) δ 8.13 (d, J = 5.3 Hz, 1H), 7.98-7.93 (m, 1H), 7.92-7.84 (m, 1H ), 7.72-7.59 (m, 1H), 7.53-7.43 (m, 2H), 7.42-7.34 (m, 1H), 7.33-7.23 (m , 1H), 6.90 (s, 1H), 6.25 (d, J = 5.4 Hz, 1H), 5.09-4.97 (m, 1H), 4.87-4.75 ( m, 1H), 4.19-4.09 (m, 1H), 4.08-3.99 (m, 1H), 4.00-3.90 (m, 2H), 3.83-3, 70 (m, 1H), 3.122.94 (m, 1H), 2.40-2.27 (m, 1H), 2.28-2.15 (m, 1H), 2.13-1.98 ( m, 2H), 1.88-1.74 (m, 2H), 1.74-1.54 (m, 4H), 1.56-1.43 (m, 1H).

Method C with modification [example 11]

Example 11. Synthesis of (rac) -rel-5- [7 - ({(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoyloxy) methyl ^ iclopentyl ^ mino ^ irazolo ^ D ^ pyrimidine ^ -yl ^ -naphthoic acid (I-99).

To the solution of (rac) -methyl rel-5- [7 - ({(1R, 2S, 3R, 4R) -2,3-dihydroxy-4 - [(sulfamoyloxy) methyl ^ iclopentyl ^ mino ^ andrazolo ^ D ^ pyrimidine ^ -yl ^ -naphthoate (0.048 g, 0.091 mmol) in DMF (2.0 ml, 26 mmol) was added 1.0 M NaOH (1.0 ml, 1.0 mmol). The mixture was stirred at room temperature for 1, 5 h, and then concentrated in vacuo as an azeotropic mixture with toluene.The crude material was purified using preparative HPLC to give (rac) -rel-5- [7 - ({(1R, 2S, 3R, 4R) -

2,3-dihydroxy-4 - [(sulfamoyloxy) methyl] cyclopentyl} amino) pyrazolo [1,5-a] pyrimidin-2-yl] -2-naphthoic acid (4.0 mg, product yield 8.5%). LCMS: (AA) M + 1 514;

¹ H NMR (400 MHz, DMSO) δ 8.71-8.63 (m, 1H), 8.55 (d, J = 8.9 Hz, 1H), 8.25-8.16 (m, 2H ), 8.09-7.98 (m, 1H), 7.98-7.90 (m, 1H), 7.89-7.79 (m, 1H), 7.75-7.63 (m , 1H), 7.55-7.25 (m, 1H), 6.79 (s, 1H), 6.33 (d, J = 5.4 Hz, 1H), 5.2-4.6 ( m, 2H), 4.18-4.05 (m, 1H), 4.06-3.90 (m, 3H), 3.80-3.68 (m, 1H), 2.40-2, 15 (m, 2H); 1.56-1.36 (m, 1H).

Method C with modification [example 12]

Example 12. Synthesis of (race) - [(1R, 2R, 3S, 4R) -4 - {[2- (3-ethynylphenyl) pyrazolo [1,5-a] pyrimidin-7yl] amino} -2,3-dihydroxycyclopentyl ] methyl rel-sulfamate (I-83).

Stage 1: (rac) -rel - [(3aR, 4R, 6R, 6aS) -6 - {[2- (3-ethynylphenyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} - 35 035020

2,2-dimethyltetrahydro-3aH-cyclopenta [b] [1,3] dioxol-4-yl] methanol (rac) -rel- {(3aR, 4R, 6R, 6aS) -2,2-dimethyl-6- [ (2- {3- [(trimethylsilyl) ethynyl] phenyl} pyrazolo [1,5a] pyrimidin-7-yl) amino] tetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl} methanol (0,067 g, 0.00014 mol; synthesized following Step 1 in method A except for the use of 4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenylethynyl-trimethylsilane instead of 1-naphthalenboronic acid) was dissolved in methanol (0.03 ml, 0.0007 mol). Potassium carbonate (21 mg, 0.00015 mol) was added and the solution was stirred at room temperature overnight. The reaction mixture was neutralized with a saturated solution of ammonium chloride and extracted with dichloromethane. The organic layer was concentrated in vacuo and purified by column chromatography (0-15% MeOH / CH ₂ Cl ₂ ) to give (rac) -rel - [(3aR, 4R, 6R, 6aS) -6 - {[2- (3 -ethynylphenyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2,2-dimethyl3aH-cyclopenta [d] [1,3] dioxol-4-yl] methanol (0.046 g, product yield 81% ) LCMS: (AA) M + 405;

¹ H NMR (400 MHz, DMSO) δ 8.25-8.05 (m, 4H), 7.52-7.44 (m, 2H), 7.00 (s, 1H), 6.25 (d , J = 5.4 Hz, 1H), 5.25-5.17 (m, 1H), 4.59-4.48 (m, 2H), 4.27 (s, 1H), 4.16- 3.99 (m, 1H), 3.65-3.44 (m, 2H), 2.48-2.38 (m, 1H), 2.28-2.19 (m, 1H), 1, 87-1.72 (m, 1H), 1.46 (s, 3H), 1.24 (s, 3H).

Stage 2: (rac) - [(1 R, 2R, 3S, 4R) -4- {[2- (3-ethynylphenyl) pyrazolo [1,5sh] pyrimidin-7-yl] amino} -2,3-dihydroxycyclopentyl] methyl Rel Sulfamate (I-83)

The title compound was synthesized from (rac) -rel - [(3aR, 4R, 6R, 6aS) -6 - {[2- (3-ethynylphenyl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2 , 2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl] methanol, following step 2 of method A. LCMS: (AA) M + 444;

¹ H NMR (400 MHz, MeOD) δ 8.22-8.16 (m, 1H), 8.13 (d, J = 5.5 Hz, 1H), 8.07-7.99 (m, 1H ), 7.55-7.34 (m, 2H), 6.78 (s, 1H), 6.32 (d, J = 5.6 Hz, 1H), 4.28-4, 17 (m, 2H), 4.16-4.07 (m, 1H), 4.07-4.02 (m, 1H), 4.01-3.94 (m, 1H), 3.55 (s, 1H) 2.60-2.29 (m, 2H); 1.67-1.47 (m, 1H).

Example 13. Compounds obtained by the method D (rac) - {(1R, 2R, 3S, 4R) -4 - [(5-chloro-2-phenylpyrazolo [1,5-a] pyrimidin-7-yl) amino ] -2,3-dihydroxycyclopentyl} methyl rel-sulfamate (I-6).

The title compound was prepared using 5-amino-3-phenylpyrazole in step 1 instead of 3 (1-naphthyl) -Sh-pyrazol-5-amine. LCMS: (AA) M + 1,454;

¹ H NMR (400 MHz, MeOD) δ 8.03 (d, J = 8.5 Hz, 2H), 7.45 (t, J = 7.3 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 6.72 (s, 1H), 6.36 (s, 1H), 4.28-4.17 (m, 2H), 4.13-3.94 (m, 3H ), 2.55-2.36 (m, 2H), 1.67-1.54 (m, 1H).

(race) - [(1 R, 2R, 3S, 4R) -4- {[5-chloro-2- (4-methoxyphenyl) pyrazolo [1,5sh] pyrimidin-7-yl] amino} -2,3-dihydroxycyclopentyl] methyl rel-sulfamate (I-14). The title compound was prepared using

5-amino-3- (4-methoxyphenyl) pyrazole in step 1 instead of 3- (1-naphthyl) -S-pyrazole-5-amine. LCMS: (AA) M + 1 484;

¹ H NMR (300 MHz, MeOD) δ 7.94 (d, J = 8.9 Hz, 2H), 7.00 (dd, J = 9.3, 2.4 Hz, 2H), 6.62 ( s, 1H), 6.32 (s, 1H), 4.29-4.16 (m, 2H), 4.12-3.93 (m, 3H), 3.84 (s, 3H), 2 57-2.33 (m, 2H); 1.66-1.52 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (2- (4-bromophenyl) -5-chloropyrazolo [1,5-a] pyrimidin-7-ylamino) -2,3-dihydroxycyclopentyl) methyl rel-sulfamate (I-8).

The title compound was prepared using 5- (4-bromophenyl) -2H-pyrazol-3-ylamine in step 1 instead of 3- (1-naphthyl) -Sh-pyrazol-5-amine. LCMS: (AA) M + 1,532;

¹ H NMR (300 MHz, DMSO) δ 8.04 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 6.95 (s, 1H) 6.35 (s, 1H), 4.16-3.88 (m, 4H), 3.79-3.68 (m, 1H), 2.33-2.17 (m, 2H), 1 61-1.37 (m, 1H).

(rac) - ((1R, 2R, 3S, 4R) -4- (5-chloro-2- (pyridin-2-yl) pyrazolo [1,5-a] pyrididin-7-ylamino) -2,3- dihydroxycyclopentyl) methyl rel-sulfamate (I-11).

The title compound was prepared using 5-pyridin-2-yl-2H-pyrazol-3-ylamine in step 1 instead of 3- (1-naphthyl) -Sh-pyrazol-5-amine. LCMS: (AA) M + 1 455;

¹ H NMR (400 MHz, MeOD) δ 8.64 (d, J = 4.9 Hz, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.01-7.85 ( m, 1H), 7.48-7.36 (m, 1H), 6.95 (s, 1H), 6.41 (s, 1H), 4.30-4.18 (m, 2H), 4 14-3.93 (m, 3H); 2.60-2.35 (m, 2H); 1.68-1.54 (m, 1H).

Method D with modification [example 14]

Example 14. (rac) - [(1 R, 2R, 3S, 4R) -2,3-dihydroxy-4- {[2- (pyridin-2-yl) pyrazolo [1,5ш] pyrimidin-7yl] amino} cyclopentyl] methyl rel-sulfamate (I-12).

(rac) - [(1R, 2R, 3S, 4R) -4 - {[5-chloro-2- (pyridin-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2 , 3-dihydroxycyclopentyl] methyl rel-sulfamate (5.0 mg, 0.011 mmol; synthesized following steps 1-4 of method D, starting from 5-pyridin-2-yl-2H-pyrazol-3-ylamine) was dissolved in methanol ( 1.00 ml, 0.0247 mol). Palladium on carbon (10%, 29.2 mg, 0.00275 mmol) was added and the suspension was purified with hydrogen gas and stirred for 3 days at room temperature under a bottle of hydrogen (1 atm). The reaction mixture was purified with nitrogen, filtered through celite and washed with methanol. The filtrate was concentrated in vacuo and purified by preparative HPLC to give ^^ - [CR ^ R ^ S ^ R) - 36 035020

2,3-dihydroxy-4 - {[2- (pyridin-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclopentyl] methyl relsulfamate (1.0 mg, yield 22%) . LCMS: (AA) M + 1 421;

¹ H NMR (400 MHz, MeOD) δ 8.72-8.61 (m, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 4.8 Hz, 1H), 7.99-7.88 (m, 1H), 7.47-7.37 (m, 1H), 7.01 (s, 1H), 6.41-6.32 (m, 1H), 4.30-4.18 (m, 2H), 4, 16-3.92 (m, 3H), 2.61-2.49 (m, 1H), 2.48-2.35 ( m, 1H); 1.68-1.56 (m, 1H).

(rac) - [(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (4-phenyl-1,3-thiazol-2-yl) pyrazolo [1,5-a] pyrididin-7yl] amino} cyclopentyl] methyl rel-sulfamate (I-31).

The title compound was obtained following method D with a modification based on (rac) [(1R, 2R, 3S, 4R) -4 - {[5-chloro-2- (4-phenyl-1,3-thiazol-2-yl ) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2,3-dihydroxycyclopentyl] methyl rel-sulfamate (synthesized following steps 1-4 of method D, starting from 3 (4-phenylthiazol-2-yl ) -S-pyrazole-5-amine). LCMS: (AA) M + 1 503;

¹ H NMR (400 MHz, MeOD) δ 8.20 (d, J = 5.5 Hz, 1H), 8.06-7.99 (m, 2H), 7.90 (s, 1H), 7, 46 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.02 (s, 1H), 6.42 (d, J = 5.5 Hz, 1H), 4.30-4.10 (m, 3H), 4.06 (t, J = 5.9 Hz, 1H), 3.99 (t, J = 5.3 Hz, 1H), 2.58-2.48 (m, 1H); 2.48-2.37 (m, 1H); 1.67-1.56 (m, 1H).

Method G [Example 15]

Example 15. Synthesis of (race) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (6-phenylpyrazin-2-yl) pyrazolo [1,5a] pyrimidin-7- yl] amino} cyclopentyl) methyl rel-sulfamate (I-121).

Step 1. (rac) - (1S, 2R, 3R, 5R) 3- (hydroxymethyl) -5 - {[2- (6-phenylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl ] amino} cyclopentane-1,2-diyl dibenzoate.

The title compound was prepared starting from (rac) - (1R, 2S, 3R, 5R) -3 - {[5-chloro-2- (6-phenylpyrazin-2yl ^ irazolo ^^^ pyrimidine Y-yl ^ mino ^^ hydroxymethyl ^ iklopentanYAD-diyl dibenzoate (obtained from 3- (6-phenylpyrazin-2-yl) -S-pyrazol-5-amine, following steps 1-3 of method D), following step 5 of method F.

Stage 2. (rac) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - {[2- (6-phenylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidin-7 -yl] amino} cyclopentyl) methyl sulfamate (I-121).

The title compound was obtained from (rac) - (1S, 2R, 3R, 5R) 3- (hydroxymethyl) -5 - {[2- (6-phenylpyrazin2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclopentane-1,2-diyl dibenzoate following step 7 of method B. LCMS: (AA) M + 1,498;

¹ H NMR (400 MHz, DMSO) δ 8.32-8.27 (m, 2H), 8.22 (d, J = 5.3 Hz, 1H), 7.87 (s, 1H), 7, 63-7.52 (m, 4H), 7.16 (s, 1H), 6.37 (d, J = 5.4 Hz, 1H), 5.08 (s, 1H), 4.86 (s , 1H), 4.19-4.11 (m, 1H), 4.08-3.95 (m, 3H), 3.84-3.74 (m, 1H), 2.42-2.19 (m, 2H); 1.59-1.47 (m, 1H).

Also obtained using method G: (rac) - [(1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ({2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl] pyrazolo [1,5-a] pyrimidin-7-yl} amino) cyclopentyl] methyl rel-sulfamate (I-122).

The title compound was prepared using (race) - (1S, 2R, 3R, 5R) -3- (hydroxymethyl) -5 - ({2- [3 (1-methyl-1 H-pyrazol-4-yl) phenyl] pyrazolo [1,5-a] pyrimidin-7-yl} amino) cyclopentan-1,2-diyl dibenzoate in step 1 instead of (rac) - (1R, 2R, 3S, 5R) -3 - {[5-chloro-2 - (6-phenylpyrazin-2-yl) pyrazolo [1,5a] pyrimidin-7-yl] amino} -5- (hydroxymethyl) cyclopentan-1,2-diyl dibenzoate. LCMS: (AA) M + 1,500;

¹ H NMR (400 MHz, DMSO) δ 8.23 (s, 2H), 8.15 (d, J = 5.3 Hz, 1H), 7.97 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.61-7.57 (m, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7, 00 (s, 1H), 6.27 (d, J = 5.4 Hz, 1H), 4.17-4.10 (m, 1H), 4.07-3.93 (m, 3H), 3 89 (s, 3H), 3.80-3.75 (m, 1H), 2.41-2.19 (m, 2H), 1.57-1.45 (m, 1H).

Example 16. Synthesis of (rac) - {(1R, 2R, 3S, 4R) -4 - [(2- {3- [2-chloro-1- (hydroxymethyl) -1-methylethyl] phenyl ^ irazolo ^ D ^ pyrimidine -yl ^ mino ^ C-dihydroxycyclopentyl ^ ethyl rel-sulfamate (I-123).

Stage 1.

The title compound was obtained from (rac) - [(3aR, 4R, 6R, 6aS) -2,2-dimethyl-6 - ({2- [3- (3-methyloxetan-3yl) phenyl] pyrazolo [1,5-a ] pyrimidin-7-yl} amino) tetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl] methanol, following step 2 in method A and adding 5 eq. pyridinium n-toluenesulfonate after adding hydrochloric acid. LCMS: (AA) M + 1,526.

Example 17

Synthesis of (se) - {(1R, 2R, 3S, 4R) -4 - [(3,6-dichloro-2- {3 - [(trifluoromethyl) sulfanyl] phenyl} pyrazolo [1,5a] pyrimidin-7-yl ) amino] -2,3-dihydroxycyclopentyl} methyl sulfamate (I-124) and (se) - {(1R, 2R, 3S, 4R) 4 - [(6-chloro-2- {3 - [(trifluoromethyl) sulfanyl ] phenyl} pyrazolo [1,5-a] pyrimidin-7-yl) amino] -2,3-dihydroxycyclopentyl} methyl sulfamate (I-125).

- 37 035020

Stage 1.

To a vial containing (8..e.) - {(1K, 2K, 38.4K) -2,3-dihydroxy-4 - [(2- {3 - [(trifluoromethyl) sulfanyl] phenyl} pyrazolo [1,5 -a] pyrimidin-7-yl) amino] cyclopentyl} methyl sulfamate (0.82 g, 0.0015 mol) and cooled to 0 ° C, N-chlorosuccinimide (126 mg, 0.000943 mol) was added as a solution to 12 ml of NN-dimethylformamide. The reaction mixture was stirred overnight with warming to room temperature. A saturated sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude material was first purified by column chromatography (eluent: methanol / methylene chloride) and then purified by HPLC to give both dichloro (LCMS: (FA) M + 1 588) and monochloro (LCMS: (FA) M + 1 554) title compounds.

Example 18. (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5a] pyrimidin-7-ylamino) cyclopentyl ) methyl sulfamate (I-101).

The title compound was obtained following Example 2a with any of the following modifications to step 2: (I) After adding 6 M hydrochloric acid to water and stirring for 1 h, the reaction mixture was made basic by adding a 1.0 M sodium hydroxide solution. The solvent was removed in vacuo and methanol was added to the crude residue. The resulting suspension was filtered through a syringe filter to remove inorganic salts, and then concentrated in vacuo. The crude material was purified using either HPLC or column chromatography (eluent: methylene chloride / methanol). (II) After adding 6 M hydrochloric acid to water and stirring for 1 h, the reaction mixture was made basic by adding a 1.0 M sodium hydroxide solution. The solvent was removed in vacuo and methanol was added to the crude residue. The resulting suspension was filtered through a syringe filter to remove inorganic salts, and then concentrated in vacuo. The crude material was purified using either HPLC or column chromatography (eluent: methylene chloride / methanol). (III) Water: tetrahydrofuran (2.6: 1) was used as a solvent instead of H ^ dimethylformamide. 12 M hydrochloric acid in water was used instead of 6 M hydrochloric acid in water. At the end, solid sodium bicarbonate was added to neutralize the reaction mixture. The mixture was diluted with water and concentrated in vacuo to remove THF, during which time a precipitate formed. The mixture was stirred for 30 minutes and the precipitate was collected by filtration over vacuo and dried in vacuo. NMR and LCMS data were consistent with those previously described for I-101.

Example 19. Form 1 of anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5 U] pyrimidin-7 -amylamino) cyclopentyl) methyl sulfamate

Stage 1:

Synthesis of tert-butyl - [({(3aR, 4R, 6aS) -2,2-dimethyl-6 - [(2- {3- (trifluoromethylthio) phenyl} pyrazolo [1,5a] pyrimidin-7-yl) amino] tetrahydro-3 aH-cyclopenta ^] [1,3] dioxol-4-yl} methoxy) sulfonyl] carba mat {(3aR, 4R, 6R, 6aS) -2,2-dimethyl-6 - [(2- {3 - (trifluoromethylthio) phenyl} pyrazolo [1,5-a] pyrimidin-7yl) amino] tetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl} methanol (3.4 g) was diluted in 2- methyltetrahydrofuran (32.0 ml) and pyridinium n-toluenesulfonate (3.34 g) was added to this solution. This contributed to the formation of a precipitate and (4-aza-1azoniabicyclo [2.2.2] oct-1-ylsulfonyl) (tert-butoxycarbonyl) azanide-1,4-diazabicyclo [2.2.2] octane (1: 1) was added to this white slurry hydrochloride (8.19 g), (prepared according to Armitage, I. et al. U.S. Patent Publication 2009/0036678 and Armitage, I. et al. Org. Lett., 2012, 14 (10), 2626-2629). The mixture was stirred at ambient temperature until HPLC showed <1% of the remaining starting material (approximately 300 min). Ethyl acetate (30 ml) and water (30 ml) were added to the reaction mixture. After stirring for 10 min, the phases were separated and the aqueous layer was again extracted with ethyl acetate (30 ml). The organic layers were combined and washed with 10% saline (30 ml) and the layers were separated. Then, the organic layer was concentrated to dryness to give an off-white solid. The solids were sent back to the acetonitrile reactor (35 ml) and stirred for 20 minutes. The solids were separated by filtration and dried in a vacuum oven under full vacuum overnight (40 ° C, 16 h) to obtain tert-butyl - [({(3aR, 4R, 6aS) -2,2-dimethyl-

6 - [(2- {3 - (trifluoromethylthio) phenyl} pyrazolo [1.5 d] pyrimidin-7-yl) amino] tetrahydro-3 aH-cyclopenta [d] [1,3] dioxol-4-yl} methoxy ) sulfonyl] carbamate (3.87 g, 88%). (LCMS: (FA2) M + 1,660).

Stage 2:

Form 1 of anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5 щ] pyrimidin-7 -ylamino) cyclopentyl) methyl sulfamate

To a solution of tert-butyl - [({((3aR, 4R, 6aS) -2,2-dimethyl-6 - [(2- {3- (trifluoromethylthio) phenyl} pyra

- 38 035020 zolo [1,5-a] pyrimidin-7-yl) amino] tetrahydro-3aH-cyclopenta [0] [1,3] dioxol-4-yl} methoxy) sulfonyl] carbamate (4.0 g) in phosphoric acid (20.0 ml) was added at 0 ° C to acetonitrile (20.0 ml), keeping the temperature below 10 ° C. This mixture was heated to ambient temperature and stirred for 4 hours. At this time, HPLC analysis showed that <1% of the starting material or intermediate reaction products remained. Ethyl acetate (20 ml) and water (20 ml) were added to the reaction mixture. After this addition was completed, saturated Na ₂ CO ₃ (80.0 ml) was added until the pH was in the range of 6-7. After stirring for 10 min, the phases were separated and the aqueous layer was again extracted with ethyl acetate (20 ml). The organic layers were combined and dried over Na ₂ SO ₄ . Then the organic layer was concentrated to 4 volumes of ethyl acetate. The solution began to precipitate for 5 minutes. This mixture was stirred for 16 hours. The resulting white solids were collected using a filter 5 minutes later. The solid was dried in a vacuum oven under full vacuum overnight (35 ° C, 16 hours). As a result, anhydrous (se) (1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7 was obtained -amylamino) cyclopentyl) methyl sulfamate. (2.85 g, 84%). XRPD data is illustrated in FIG. 1; DSC data is illustrated in FIG. 2; TGA data is illustrated in FIG. 3; Raman data is illustrated in FIG. 4, 5A, 6A and 7A.

Form 1 can also be obtained as follows:

To a solution of tert-butyl - [({((3aR, 4R, 6aS) -2,2-dimethyl-6 - [(2- {3- (trifluoromethylthio) phenyl} pyrazolo [1,5-a] pyrimidin-7-yl ) amino] tetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl} methoxy) sulfonyl] carbamate (2.4 g) in acetonitrile (12.0 ml) at 0 ° C was added phosphoric acid (12 , 0 ml), maintaining the temperature below 10 ° C. This mixture was heated to ambient temperature and stirred for 4 hours. At this time, HPLC analysis showed that <1% of the starting material or intermediate reaction products remained. Ethyl acetate (12 ml) and water (12 ml) were added to the reaction mixture. After this addition was completed, saturated Na ₂ CO ₃ (48.0 ml) was added until the pH was in the range of 6-7. After stirring for 10 min, the phases were separated and the aqueous layer was again extracted with ethyl acetate (20 ml). Then, the combined organic layers were washed with water (24 ml). Then acetonitrile (24 ml) was added to the organic layer, and then it was concentrated to -10 volumes. Then acetonitrile (24 ml) was added to the organic layer and concentrated to -10 volumes. Then acetonitrile (24 ml) was added to the organic layer and concentrated to -5 volumes of acetonitrile. Form 1 anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3 (trifluoromethylthiophenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate (obtained in step 2 above). The solution began to precipitate for 5 minutes, this mixture was stirred for 16 hours, the resulting white solids were collected using a filter for 5 minutes, the solid was dried in a vacuum oven under full vacuum overnight (35 ° C, 16 h). As a result, anhydrous (se) - (1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3 (trifluoromethylthio) phenyl) was obtained ) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate (1.35 g, 71%). Analytical data are comparable with form 1.

Form 1 can also be obtained as follows:

To form 1 anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo ^^^ pyrimidine ^ -amino ^ cyclopentyl ^ ethyl sulfonate (5.0 g) was added acetonitrile (32 ml) and water (8 ml). This mixture was heated to 50 ° C., whereby all solids were in solution. Water (40 ml) was added to this solution, keeping the temperature solution at 50 ° C. Then the solution was seeded with form 1 of anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio ^ enyl ^ irazolo ^^^ pyrimidine ^ -ylamino ^ iclopentyl ^ ethyl sulfamate (obtained in step 2 above). The seed was not dissolved, and then the mixture was cooled to 22 ° C for 12 hours. The resulting white solids were collected using a filter for 5 minutes. the substance was dried in a vacuum oven under full vacuum overnight (35 ° C, 16 h) with the release of the product of form 1 anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2 - (3- (trifluoromethylthio) phenyl) pyrazolo [1,5a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfam ata (4.25 g, 85%). Analytical data are comparable to form 1.

Example 20. Form 2 monohydrated (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3 (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7 -amylamino) cyclopentyl) methyl sulfamate

To a solution of tert-butyl - [({((3aR, 4R, 6aS) -2,2-dimethyl-6 - [(2- {3- (trifluoromethylthio) phenyl} pyrazolo [1,5-a] pyrimidin-7-yl ) amino] tetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl} methoxy) sulfonyl] carbamate (5.0 g) in acetonitrile (25.0 ml) at 0 ° C was added phosphoric acid (25 , 0 ml), maintaining the temperature below 10 ° C. This mixture was heated to ambient temperature and stirred for 4 hours. At this time, HPLC analysis showed that <1% of the starting material or intermediate reaction products remained. Ethyl acetate (25 ml) and water (25 ml) were added to the reaction mixture. After this addition was completed, saturated Na ₂ CO ₃ (100.0 ml) was added until the pH was in the range of 6-7. After stirring for 10 min, the phases were separated and the aqueous layer was again extracted with ethyl acetate (25 ml). Then, the combined organic layers were washed with 10% saline (50 ml). The organic layers were dried over Na ₂ SO ₄ . Then the organic layer con

- 39 035020 centered to 4 volumes of ethyl acetate. The solution began to precipitate for 5 minutes. This mixture was stirred for 16 hours. The resulting white solids were collected using a filter for 5 minutes. The solid was dried in a vacuum oven under full vacuum overnight (35 ° C, 16 hours). As a result, monohydrated form 2 (s.e.) - ((1R, 2R, 3S, 4R) -

2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate (3.04 g, 77%). XRPD data is illustrated in FIG. 8; DSC data is illustrated in FIG. 9; TGA data is illustrated in FIG. 10; Raman data is illustrated in FIG. 11, 5B, 6B and 7B.

Form 2 can also be obtained as follows:

Form 1 anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-n] pyrimidin-7-ylamino ) cyclopentyl) methyl sulfamate (1.5 g) was dissolved in 90: 10 / MeCM: water (25.0 ml) at 50 ° C. The solution was rapidly cooled to 5 ° C. Water (20 ml) was added to the solution while maintaining the temperature. Then the reaction mixture was seeded with form 2 of monohydrated (3.e.) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a ] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate (prepared as described above). The solution was stirred for 2 hours at 5 ° C and allowed to remain cloudy. Then, additional water (11.25 ml) was added and the mixture was stirred for 16 hours. Then, the slurry was filtered and dried for 48 hours. As a result, monohydrated (se) - (2), (1R, 2R, 3S, 4R) -2 was obtained , 3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5th] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate (1.21 g, 95%). Analytical data are comparable to form 2.

Example 21. Comparative suspension studies

Approximately 10 mg of a 1: 1 mixture of Form 1 anhydrous (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3 (trifluoromethylthio) phenyl) pyrazolo [1,5-n ] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate and form 2 monohydrated (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-d] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate was placed in a vial and 100 μl of the solvents listed in table. 5 below (which were previously saturated in Form 1) was added to the vial. The vials were shaken at the temperature shown below for 60 hours. Other solids remaining at this time were separated by centrifugation and analyzed by XRPD.

Table 5. Conclusion of Comparative Suspension Studies

Temperature (° C) Composition The form, % % Water submitted 5 90 10 Form 2 5 80 twenty Form 2 5 70 thirty Form 2 Environment 90 10 Mixture Environment 80 twenty Mixture Environment 70 thirty Mixture fifty 90 10 Form 1 fifty 80 twenty Form 1 fifty 70 thirty Form 1

In all solvent systems studied, Form 2 was separated at 5 ° C and Form 1 was separated at 50 ° C, demonstrating that the separation of the desired form can be controlled by temperature.

Example 22. Obtaining a solution of (se) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-d] pyrimidin-7 -amylamino) cyclopentyl) methyl sulfamate for parenteral administration

Composition Composition (se - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-y] pyrimidin-7-ylamino) cyclopentyl ) methyl sulfamate for injection (intravenous or subcutaneous) is shown in table 6

- 40 035020

Table 6. The quantitative composition of the composition of a sterile solution for parenteral administration

Component Function Amount (mg / ml) Anhydrous Citric Acid, USP excipient 9.61 Sulfobutyl esters β- cyclodextrin, sodium salts (Captisol®) (Ligand Pharmaceuticals Inc) excipient fifty Form 1 anhydrous s.e.) - ((1 R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3 (trifluoromethylthio) phenyl) pyrazolo [1,5a] pyrimidin-7- ilamino) cyclopentyl) methyl sulfamate 2 Sodium hydroxide pH regulator sufficient amount up to pH 3.3 ± 0.5 Water for injections solvent sufficient amount up to 1 ml

A batch of sterile solution (8.c.) - ((1K, 2K, 38.4K) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio ^ enyl ^ irazolo ^ b ^ pyrimidin-T-ylamino ^ iklopentyl ^ ethyl sulfamate for parenteral administration was obtained by performing the following steps:

1) Calculate the desired amount of excipients and solvent per batch using the quantitative composition shown in the table. 3.

2) The calculated amount of anhydrous citric acid was added to 75% of the calculated amount of sterile water for injection and mixed until the citric acid was completely dissolved.

3) A calculated amount of Captisol® was added to the solution and mixed until Captisol® was completely dissolved.

4) The calculated amount of Form 1 of anhydrous ^. S.) - ((1K, 2K, 38.4I) -2,3-dihydroxy-4 (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a ] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate to the solution and stirred until complete dissolution.

5) The pH of the solution was adjusted to the target 3.3 ± 0.5 using a sodium hydroxide solution.

6) The volume of the solution was adjusted to a target concentration of 2.0 mg / ml (sc) - ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1, 5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate using sterile water for injection.

7) The bulk of the compound solution was filtered using a 0.45 μM light filter and then a 0.2 μM sterilizing filter for pre-filtering and sterilization, respectively.

8) Under sterile conditions, sterile and pyrogen-free vials were filled with a sterile solution.

9) The filled vials were sealed using sterile rubber stoppers and an additional closure was applied to prevent illegal opening of containers using sterile aluminum edges with polypropylene caps.

Biological tests

Analysis of HTRF ubiquitin-activating enzyme (UAE)

The UAE enzyme reaction mixture was 50 μl and contained 50 mmol of HEPES (pH 7.5), 0.05% BSA, 2.5 mM MgCl ₂ , 0.1 μM ATP, 8 nM GST-Ubc-2, 35 nM labeled ubiquitin , 1 nM recombinant human UAE or UAE mice. The compounds for this hUAE IC ₅₀ assay were tested at 10 point 3-fold dilution. The highest concentration point for this analysis was 1 μM. Each compound was arranged in order in duplicate on the same plate. The enzyme reaction mixture was incubated for 90 min at room temperature (24 ° C) in a 384 well plate until complete with stop reagent (0.1 M HEPES / 0.05% Twccn 20, 20 mmol EDTA, 410 mm KF, 0.5 nM Eu Cryptatc anti-FLAG M2-K antibody (cis-bio International), 8 μg / ml Anti-GST XL-APC (Prozymc)). After incubation for 120 min, a FRET quantitative analysis was performed on Phcrostar (BMG).

From the Phcrastar data files, the% inhibition was calculated compared to the main controls on the plate. The drug response data was further processed in Gcncdata Condosco, which performed a 4 parameter logistic model and determined IC ₅₀ (intersection at 50% inhibition) for each compound.

The results are shown in the following table. For compounds whose values are marked with an asterisk (*), UAE mice were used. For all other compounds, human UAE was used.

- 41 035020

Connection number Example Number % inhibition @ 0.111 μM 1C ₅₀ ^t 1-001 8 72 * AT I-002 2B 100* AND I-003 8 100 AND I-004 5 31 WITH I-005 8 100* AND I-006 thirteen 23 WITH I-007 8 99 AND I-008 thirteen 28 WITH I-009 4 42 WITH 1-010 7 100 AND 1-011 thirteen 49 * WITH 1-012 14 61 * AT 1-013 8 84 AT 1-014 thirteen thirty WITH 1-015 8 100 AND 1-016 7 99 AND 1-017 7 100 AND 1-018 7 100 AND 1-019 7 100 AND I-020 7 100 AND 1-021 7 97 AND I-022 7 100 AND I-023 7 96 AT I-024 7 98 AND I-025 7 93 AT I-026 7 100 AND I-027 7 100 AND I-028 7 99 AND I-029 7 100 AND I-030 7 99 AND 1-031 14 100 AND I-032 7 100 AND I-033 7 98 AND I-034 7 100 AND I-035 7 100 AND I-036 7 100 AND

- 42 035020

1-037 7 100 AND 1-038 7 100 AND 1-039 7 100 AND 1-040 7 100 AND 1-041 7 99 AND I-042 7 100 AND I-043 7 100 AND I-044 7 100 AND I-045 7 100 AND I-046 7 100 AND I-047 9 100 AND I-048 10 100 AND I-049 7 100 AND I-050 7 100 AND 1-051 7 90 AT I-052 9 100 AND I-053 7 100 AND I-054 7 100 AND I-055 7 100 AND I-056 7 100 AND I-057 7 100 AND I-058 9 100 AND I-059 7 94 AT I-060 7 89 AT 1-061 7 100 AND I-062 7 100 AND I-063 9 100 AND I-064 9 96 AT I-065 7 100 AND I-066 7 100 AND I-067 7 100 AND I-068 7 95 AT I-069 7 84 AT I-070 7 99 AND 1-071 7 100 AND I-072 7 100 AND I-073 7 91 AT I-074 7 98 AT I-075 7 1 AND I-076 7 100 AND I-077 7 100 AND I-078 7 100 AND I-079 9 75 AT I-080 9 80 AT 1-081 7 100 AND I-082 7 100 AND I-083 12 100 AND I-084 7 100 AND I-085 9 99 AND I-086 9 99 AND

- 43 035020

1-087 7 100 AND 1-088 7 97 AT 1-089 6 27 WITH 1-090 7 100 AND 1-091 7 100* AND I-092 7 100 AND I-093 9 100 AND I-094 7 100 AND I-095 7 70 AT I-096 9 100 AND I-097 9 100 AND I-098 2a 100 AND I-099 eleven 100 AND 1-100 7 100 AND 1-101 7 99 AND 1-102 7 100 AND 1-103 7 100 AND 1-104 9 100 AND 1-105 9 100 AND 1-106 9 100 AND 1-107 9 100 AND 1-108 3 100 AND 1-109 9 100 AND 1-110 9 100 AND 1-111 9 100 AND 1-112 9 100 AND 1-113 7 100 AND 1-114 9 99 AND 1-115 9 100 AND 1-116 7 100 AND 1-117 7 92 AT 1-118 7 100 AND 1-119 7 99 AND 1-120 7 100 AND 1-121 fifteen 100 AND 1-122 fifteen 97 AND 1-123 sixteen 100 AND 1-124 17 twenty WITH 1-125 17 fifty WITH t A means IC50 <10 nM B means 1OnM <1С ₅ о ^ YuO nM C means 100 nM <1C ₅₀ 1 μM

While the number of embodiments of the present invention has been described, it is clear that the presented examples can be modified to express other embodiments that use the chemical compounds and methods of the present invention. Thus, it should be appreciated that the scope of the present invention has been presented herein as an example and is not intended to be limited to the specific described embodiments.

Claims (15)

CLAIM 1. The compound, which is (rac) - (2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate or one from its enantiomers ((1K, 2K, 38.4K) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate or ((18.28.3H, 48) -2,3-dihydroxy-4- (2- (3 (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate as follows - general structures: or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is ((1K, 2H, 38.4K) -2,3-dihydroxy-4- (2- (3 (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7 -amylamino) cyclopentyl) methyl sulfamate or ((18.28.3K, 48) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7- ilamino) cyclopentyl) methyl sulfamate. 3. The compound according to claim 1, which is a pharmaceutically acceptable salt ((1R, 2R, 3S, 4R) - 2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate or ((1S, 2S, 3R, 4S) -2 , 3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate. - 44 035020 4. The compound is ((1K, 2K, 38.4K) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate of formula I-101 1-101, or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 4, which is ((1K, 2K, 38.4J) -2,3-dihydroxy-4- (2- (3 (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7 -amylamino) cyclopentyl) methyl sulfamate of the formula I-101. 6. The compound according to claim 4, which is a pharmaceutically acceptable salt of ((1R, 2R, 3S, 4R) 2,3-dihydroxy-4- (2- (3 - (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate of the formula I-101. 7. A compound representing the crystalline form 1 of anhydrous ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7- ilamino) cyclopentyl) methyl sulfamate, characterized in that its X-ray powder diffraction pattern (XRPD) has peaks at 2θ angles of 16.4, 18.0, 20.5 and 20.7 °. 8. The compound according to claim 7, which at least 95 wt.% Is a crystalline form 1 of anhydrous ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio ) phenyl) pyrazolo [1,5a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate. 9. The compound is a crystalline form of 2 monohydrated ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidine- 7-ylamino) cyclopentyl) methyl sulfamate, characterized in that its X-ray powder diffraction pattern (XRPD) has peaks at 2θ angles of 6.7, 17.6, 20.0 and 21.6 °. 10. The compound according to claim 9, which at least 95 wt.% Is a crystalline form of 2 monohydrated ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio ) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate. 11. A pharmaceutical composition suitable for inhibiting the activity of a ubiquitin-activating enzyme (UAE), containing the compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition suitable for inhibiting the activity of a ubiquitin-activating enzyme (UAE) containing at least one compound selected from crystalline form 1 of anhydrous ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4- (2- (3- (trifluoromethylthio) phenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate according to claim 7 and crystalline form 2 monohydrated ((1 R, 2R, 3S, 4R) -2.3 -dihydroxy-4- (2- (3 - (trifluoromethylthio) phenyl) pyrazolo [1,5a] pyrimidin-7-ylamino) cyclopentyl) methyl sulfamate according to claim 9, and a pharmaceutically acceptable carrier. 13. The use of a compound according to any one of claims 1 to 10 in the treatment of cancer in a patient in need of such treatment. 14. The use of claim 13, wherein the cancer is pancreatic cancer, bladder cancer, colon and rectal cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, bronchial and lung cancer, ovarian cancer, cervical cancer, endometrial cancer, gastric cancer, esophageal cancer, neck and head cancer, nasopharyngeal cancer, oral cancer, thyroid cancer, melanoma, neuroendocrine cancer, brain tumor, bone cancer, soft tissue sarcoma, acute myelocytic leukemia chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, multiple myeloma, amyloidosis, Waldenstrom macroglobulinemia, myelodysplastic syndrome, or myeloproliferative syndromes. 15. The compound is {(3aR, 4R, 6R, 6aS) -2,2-dimethyl-6 - {[2- {3- (trifluoromethylthio) phenyl} pyrazolo [1,5-a] pyrimidin-7-yl ) amino] tetrahydro-3aH-cyclopenta [b] [1,3] dioxol-4yl} methanol, or a pharmaceutically acceptable salt thereof.